GDF-8 inhibitors

ABSTRACT

Described are GCF-8 inhibitors of the formula (I), 
                         
and pharmaceutically acceptable salts thereof, wherein n, R 1 , R 2 , R 5 , R 6 , X and Z are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for inhibiting GDF-8 in a cell and methods for treating a patient suffering from a disease or disorder, wherein the patient would therapeutically benefit from an increase in mass or strength of muscle tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 14/046,834,filed Oct. 4, 2013, which claims the benefit of priority of U.S.Provisional Patent Application Ser. No. 61/710,449, filed Oct. 5, 2012,which applications are hereby incorporated herein by reference in theirentirety.

BACKGROUND OF THE DISCLOSURE

Field of the Disclosure

This disclosure relates to pharmaceutically active compounds and methodsfor their use. In particular the disclosure relates to kinaseinhibitors. In one aspect the compounds also inhibit the signaling ofcytokines such as TGF-β1, Growth Differentiation Factor-8 (GDF-8) andother members of the TGF-βs, activins, inhibins, bone morphogeneticproteins and Mullerian-inhibiting substance, that signal through afamily of transmembrane kinase receptors. The inhibitors are useful fortreating inflammatory disorders, such as inflammatory or obstructiveairway diseases, such as pulmonary hypertension, pulmonary fibrosis,liver fibrosis; and cancer. The inhibitors are particularly useful fordiagnosing, preventing, or treating human or animal disorders in whichan increase in muscle tissue would be therapeutically beneficial.Exemplary disorders include neuromuscular disorders (e.g., musculardystrophy and muscle atrophy), congestive obstructive pulmonary disease,muscle wasting syndrome, sarcopenia, and cachexia; adipose tissuedisorders (such as obesity); type 2 diabetes; and bone degenerativedisease (such as osteoporosis).

Summary of the Related Art

Growth and Differentiation Factor-8 (GDF-8), also known as myostatin,and TGF-β1 are a members of the Transforming Growth Factor-beta (TGF-β)superfamily of structurally related growth factors, all of which possessphysiologically important growth-regulatory and morphogenetic properties(Kingsley et al. (1994) Genes Dev., 8: 133-46; Hoodless et al. (1998)Curr. Topics Microbiol. Immunol., 228: 235-72). For example, activationof TGF-β1 signaling and expansion of extracellular matrix are early andpersistent contributors to the development and progression of fibroticdisorders, such as involved in chronic renal disease and vasculardisease. Border W. A., et al, N. Engl. J. Med., 1994; 331(19), 1286-92.GDF-8 is a negative regulator of skeletal muscle mass, and there isconsiderable interest in identifying factors which regulate itsbiological activity. For example, GDF-8 is highly expressed in thedeveloping and adult skeletal muscle. The GDF-8 null mutation intransgenic mice is characterized by a marked hypertrophy and hyperplasiaof the skeletal muscle (McPherson et al. (1997) Nature, 387: 83-90).Similar increases in skeletal muscle mass are evident in naturallyoccurring mutations of GDF-8 in cattle (Ashmore et al. (1974) Growth,38: 501 507; Swatland and Kieffer (1994) J. Anim. Sci., 38: 752-757;McPherron and Lee (1997) Proc. Natl. Acad. Sci. USA, 94: 12457-12461;and Kambadur et al. (1997) Genome Res., 7: 910-915). Since GDF-8 isexpressed in both developing and adult muscles, it is not clear whetherit regulates muscle mass during development or in adults. Thus, thequestion of whether or not GDF-8 regulates muscle mass in adults isimportant from a scientific and therapeutic perspective. Recent studieshave also shown that muscle wasting associated with HIV-infection inhumans is accompanied by increases in GDF-8 protein expression(Gonzalez-Cadavid et al. (1998) PNAS, 95: 14938-43). In addition, GDF-8can modulate the production of muscle-specific enzymes (e.g., creatinekinase) and modulate myoblast cell proliferation (WO 00/43781).

A number of human and animal disorders are associated with loss orfunctional impairment of muscle tissue, including muscular dystrophy,muscle atrophy, congestive obstructive pulmonary disease, muscle wastingsyndrome, sarcopenia, and cachexia. To date, very few reliable oreffective therapies exist for these disorders. However, the terriblesymptoms associated with these disorders may be substantially reduced byemploying therapies that increase the amount of muscle tissue inpatients suffering from the disorders. While not curing the conditions,such therapies would significantly improve the quality of life for thesepatients and could ameliorate some of the effects of these diseases.Thus, there is a need in the art to identify new therapies that maycontribute to an overall increase in muscle tissue in patients sufferingfrom these disorders.

In addition to its growth-regulatory and morphogenetic properties inskeletal muscle, GDF-8 may also be involved in a number of otherphysiological processes, including glucose homeostasis in thedevelopment of type 2 diabetes and adipose tissue disorders, such asobesity. For example, GDF-8 modulates pre-adipocyte differentiation toadipocytes (Kim et al. (2001) BBRC, 281: 902-906).

There are also a number of conditions associated with a loss of bone,including osteoporosis, especially in the elderly and/or postmenopausalwomen. Currently available therapies for these conditions work byinhibiting bone resorption. A therapy that promotes new bone formationwould be a desirable alternative to or addition to, these therapies.

Like TGF-β-1, -2, and -3, the GDF-8 protein is synthesized as aprecursor protein consisting of an amino-terminal propeptide and acarboxy-terminal mature domain (McPherron and Lee, (1997) Proc. Natl.Acad. Sci. USA, 94: 12457-12461). Before cleavage, the precursor GDF-8protein forms a homodimer. The amino-terminal propeptide is then cleavedfrom the mature domain. The cleaved propeptide may remain noncovalentlybound to the mature domain dimer, inactivating its biological activity(Miyazono et al. (1988) J. Biol. Chem., 263: 6407-6415; Wakefield et al.(1988) J. Biol. Chem., 263; 7646-7654; and Brown et al. (1990) GrowthFactors, 3: 35-43). It is believed that two GDF-8 propeptides bind tothe GDF-8 mature dimer (Thies et al. (2001) Growth Factors, 18:251-259). Due to this inactivating property, the propeptide is known asthe “latency-associated peptide” (LAP), and the complex of mature domainand propeptide is commonly referred to as the “small latent complex”(Gentry and Nash (1990) Biochemistry, 29: 6851-6857; Derynck et al.(1995) Nature, 316: 701-705; and Massague (1990) Ann. Rev. Cell Biol.,12: 597-641). Other proteins are also known to bind to GDF-8 orstructurally related proteins and inhibit their biological activity.Such inhibitory proteins include follistatin, and potentially,follistatin-related proteins (Gamer et al. (1999) Dev. Biol., 208:222-232). The mature domain is believed to be active as a homodimer whenthe propeptide is removed.

GDF-8 is highly conserved in sequence and in function across species.The amino acid sequence of murine and human GDF-8 is identical, as isthe pattern of mRNA expression (McPherron et al. (1997) Nature 387:83-90; Gonzalez-Cadavid et al. (1998) Proc. Natl. Acad. Sci. USA 95:14938-14943). This conservation of sequence and function suggests thatinhibition of GDF-8 in humans is likely to have a similar effect toinhibition of GDF-8 in mice.

GDF-8 is involved in the regulation of many critical biologicalprocesses. Due to its key function in these processes, GDF-8 may be adesirable target for therapeutic intervention.

For example, U.S. Pat. No. 7,320,789, shows that GDF-8 antibodies inmouse models canincrease muscle strength (e.g., for treatingsarcopenia), increase muscle mass and strength in dystrophic muscle(e.g., for treating Duchenne's muscular dystrophy), increase bone massand bone density (e.g., for prevention and treatment of osteoporosis),augment bone healing (e.g., for treating an established muscle or bonedegenerative disease (e.g., fracture repair and spine fusion, preventingthe decline in bone mass, microarchitecture and strength associated withestrogen deficiency, increasing trabecular bone density), and are usefulfor treatment of metabolic disorders such as type 2 diabetes, impairedglucose tolerance, metabolic syndrome (e.g., syndrome X), insulinresistance induced by trauma (e.g., burns), and adipose tissue disorders(e.g., obesity).

In particular, therapeutic agents that inhibit the activity of GDF-8 maybe used to treat human or animal disorders in which an increase inmuscle tissue would be therapeutically beneficial, particularly muscleand adipose tissue disorders, bone degenerative diseases, neuromusculardisorders, and diabetes, as discussed above.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure relates to compounds of theformula (I),

and pharmaceutically acceptable salts thereof, wherein n, R¹, R², R⁵,R⁶, X and Z are defined herein.

In another aspect, disclosed are pharmaceutical compositions comprisinga compound or pharmaceutically acceptable salt of a compound accordingto formula (I) and a pharmaceutically acceptable carrier, excipient, ordiluent.

In another aspect, disclosed are methods for inhibiting GDF-8 in a cellcomprising contacting the cell with an effective amount of a compound orpharmaceutically acceptable salt of a compound according to formula (I)or a pharmaceutical composition comprising a compound orpharmaceutically acceptable salt of a compound according to formula (I)and a pharmaceutically acceptable carrier, excipient, or diluent.

In another aspect, disclosed are methods for treating a patientsuffering from a disease or disorder, wherein the patient wouldtherapeutically benefit from an increase in mass or strength of muscletissue, comprising administering to a patient a therapeuticallyeffective amount of a compound or pharmaceutically acceptable salt of acompound according to formula (I) or a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt of a compoundaccording to formula (I) and a pharmaceutically acceptable carrier,excipient, or diluent.

In another aspect, disclosed are methods for increasing muscle mass in amammal comprising administering a therapeutically effective amount of acompound or pharmaceutically acceptable salt of a compound according toformula (I) or a pharmaceutical composition comprising a compound orpharmaceutically acceptable salt of a compound according to formula (I)and a pharmaceutically acceptable carrier, excipient, or diluent.

In another aspect, disclosed are methods for increasing muscle strengthin a mammal comprising administering a therapeutically effective amountof a compound or pharmaceutically acceptable salt according to formula(I) or a pharmaceutical composition comprising a compound orpharmaceutically acceptable salt according to formula (I) and apharmaceutically acceptable carrier, excipient, or diluent.

In another aspect, disclosed are methods for increasing trabecular bonedensity in a patient in need thereof, comprising administering atherapeutically effective amount of a compound or pharmaceuticallyacceptable salt according to formula (I) or a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt according toformula (I) and a pharmaceutically acceptable carrier, excipient, ordiluent.

DETAILED DESCRIPTION OF THE DISCLOSURE

In one aspect, the disclosure comprises pharmaceutical compounds offormula (I),

and pharmaceutically acceptable salts thereof, wherein

-   -   X is C(H) or N;    -   R¹ and R² are each independently hydrogen, halogen, cyano,        nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₃₋₈cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R¹⁰, or        —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR^(a)R^(a), —C(O)R,        —C(O)OR, —C(O)NR^(a)R^(a), —S(O)₂NR^(a)R^(a), —OC(O)R,        —N(R)C(O)R, —OC(O)OR, —O(CH₂)_(m)C(O)NR^(a)R^(a), —N(R)C(O)OR,        —N(R)C(O)NR^(a)R^(a), —N(R)S(O)₂NR^(a)R^(a) or —N(R)S(O)₂R;    -   or when R¹ and R² are attached to adjacent carbon atoms they are        optionally taken together with the atoms to which they are        attached to form a 5- or 6-membered ring optionally substituted        with one or two groups that are each independently halogen, oxo,        oxime, imino, C₁₋₆alkyl, C₁₋₆haloalkyl, or —R¹⁰;    -   each R^(a) is independently R or, two R^(a) together with the        nitrogen atom to which they are attached form a 3-8 membered        heterocyclyl group, optionally including 1-4 additional        heteroatoms selected from O, N and S and optionally substituted        with 1-4 R groups;    -   each R^(b) is independently halogen, cyano, oxo, C₁₋₆alkyl,        C₁₋₆haloalkyl, or —OR;    -   m is 0, 1 or 2;    -   n is 1, 2, 3 or 4;    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁₋₆alkyl        optionally substituted with 1-3 R^(b), C₁₋₆haloalkyl,        C₃₋₈cycloalkyl optionally substituted with one or two R^(b),        heteroaryl optionally substituted with one or two R^(b), aryl        optionally substituted with one or two R^(b),        heterocyclyl(C₁₋₆alkyl) optionally substituted with one or two        R^(b), —OR, —SR, —NR^(a)R^(a), —OC(O)R, —C(O)NR^(a)R^(a),        —OC(O)NR^(a)R^(a), —C(O)OR, —N(R)C(O)R, —N(R)S(O)₂R, or R⁵ and        R⁶ are optionally taken together with the atoms to which they        are attached to form a 5- or 6-membered ring optionally        including 1-3 additional heteroatoms selected from O, N and S        and optionally substituted with 1-4 R^(b);    -   Z is (a) a fused bicyclic ring of the formula,

-   -    wherein        -   ring A is a phenyl or 5- or 6-membered heteroaryl,        -   ring B is a 5- or 6-membered heterocyclyl or 5- or            6-membered heteroaryl;        -   or (b) pyridinyl or pyrimidinyl,        -   wherein            -   Z is optionally substituted by one or two groups that                are each independently halogen, C₁₋₆alkyl,                C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl,                heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),                heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl),                heteroaryl(C₁₋₆alkyl), —R^(Z), or —C₁₋₆alkyl-R^(Z),                wherein the C₃₋₈cycloalkyl, heterocyclyl, aryl,                heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),                heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), and                heteroaryl(C₁₋₆alkyl) are each optionally substituted by                one or two groups that are each independently halogen,                C₁₋₆alkyl, or R^(Z);            -   and R^(Z) is cyano, —CF₃, —OR, —SR, —NR^(a)R^(a),                —C(O)R, —C(O)OR, —C(O)NR^(a)R^(a), —S(O)₂NR^(a)R^(a),                —S(O)₂R⁰, —OC(O)R, —N(R)C(O)R, —OC(O)OR,                —OC(O)NR^(a)R^(a), —N(R)C(O)OR, —N(R)C(O)NR^(a)R^(a),                —N(R)S(O)₂R, or —OP(O)(OR)₂;            -   or Z is (c) phenyl substituted with 1, 2, 3, 4, or 5                groups that are each independently a halogen;        -   wherein each R is independently hydrogen, C₁₋₆alkyl,            C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl,            heteroaryl, heteroaryl(heteroaryl)-, heterocyclyl(aryl)-,            heteroaryl(heterocyclyl)-, C₃₋₈cycloalkyl(C₁₋₆alkyl),            heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), or            heteroaryl(C₁₋₆alkyl), each optionally substituted by 1-5            groups that are each independently R^(b), —OR⁰, —SR⁰,            —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂,            —OC(O)R⁰, —N(R⁰)C(O)R⁰, —OC(O)OR⁰), —O(CH₂)_(m)C(O)N(R⁰)₂,            —N(R⁰)C(O)OR⁰), —N(R⁰)C(O)N(R⁰)₂, or —N(R⁰)S(O)₂R⁰;        -   and each R⁰ is independently hydrogen, C₁₋₆haloalkyl,            C₁₋₆alkyl optionally substituted with 1-3 R^(b),            C₃₋₈cycloalkyl optionally substituted with one or two R^(b)            or, alternatively two R⁰ together with a nitrogen atom to            which they are bound (for example when R is —C(O)N(R⁰)₂)            form a 3-8 membered heterocyclyl group, optionally including            1-4 additional heteroatoms selected from O, N and S and            optionally substituted with 0-3 R^(b) and R groups.

For example, in one embodiment, the disclosure provides pharmaceuticallyactive compounds and pharmaceutically acceptable salts thereof asdescribed above, in which

-   -   n is 1;    -   X is C(H) or N;    -   R¹ and R² are each independently hydrogen, halogen, cyano,        nitro, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl,        C₃₋₈cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R¹⁰, or        —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR^(a)R^(a), —C(O)R,        —C(O)OR, —C(O)NR^(a)R^(a), —S(O)₂NR^(a)R^(a), —OC(O)R,        —N(R)C(O)R, —OC(O)OR, —OC(O)NR^(a)R^(a), —N(R)C(O)OR,        —N(R)C(O)NR^(a)R^(a), or —N(R)S(O)₂R;    -   or when R¹ and R² are attached to adjacent carbon atoms they are        optionally taken together with the atoms to which they are        attached to form a 5- or 6-membered heteroaryl group optionally        substituted with one or two groups that are each independently        halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, or R¹⁰;    -   each R^(a) is independently R or, two R^(a) together with the        nitrogen atom to which they are attached form a 3-8 membered        heterocyclyl group, optionally including 1-4 additional        heteroatoms selected from O, N and S and optionally substituted        with 1-4 R groups;    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, —OR, —SR, —NR^(a)R^(a), —OC(O)R,        —N(R)C(O)R, or —N(R)S(O)₂R;    -   Z is (a) a fused bicyclic ring of the formula,

-   -    wherein        -   ring A is a phenyl or 5- or 6-membered heteroaryl,        -   ring B is a 5- or 6-membered heterocyclyl or 5- or            6-membered heteroaryl, and wherein            -   Z is optionally substituted by one or two groups that                are each independently halogen, C₁₋₆alkyl,                C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl,                heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),                heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl),                heteroaryl(C₁₋₆alkyl), —R^(Z), or —C₁₋₆alkyl-R^(Z),                wherein the C₃₋₈cycloalkyl, heterocyclyl, aryl,                heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),                heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), and                heteroaryl(C₁₋₆alkyl) are each optionally substituted by                one or two groups that are each independently halogen,                C₁₋₆alkyl, or —R^(Z);            -   and R^(Z) is —OR, —SR, —NR^(a)R^(a), —C(O)R, —C(O)OR,                —C(O)NR^(a)R^(a), —S(O)₂NR^(a)R^(a), —OC(O)R,                —N(R)C(O)R, —OC(O)OR, —OC(O)NR^(a)R^(a), —N(R)C(O)OR,                —N(R)C(O)NR^(a)R^(a), —N(R)S(O)₂R, or —OP(O)(OR)₂;            -   or (b) phenyl substituted with 1, 2, 3, 4, or 5 groups                that are each independently a halogen;        -   and each R is independently hydrogen or C₁₋₆alkyl,            C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl,            heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),            heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), or            heteroaryl(C₁₋₆alkyl), each optionally substituted by one or            two groups that are each independently —OR⁰, —SR⁰, —N(R⁰)₂,            —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰,            —N(R⁰)C(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰,            —N(R⁰)C(O)N(R⁰)₂, or —N(R⁰)S(O)₂R⁰, wherein each R⁰ is            independently hydrogen or C₁₋₆alkyl.

The disclosure further comprises subgenera of formula (I) in which thesubstituents are selected as any and all combinations of one or more ofstructural formula (I), n, R¹, R², R⁵, R⁶, X, Z, R^(a), R^(b), R^(Z) Rand R⁰ as defined herein, including without limitation, the following:

Structural Formula I is One of Formulae (Ia)-(Ih):

X in any of Formulae (I), (Ia), and (Ib) is Selected from One of theFollowing Groups (1a)-(1b):

-   -   (1a) X is C(H).    -   (1b) X is N.

R¹ in any of Formulae (I) and (Ia)-(Ix) is Selected from One of theFollowing Groups (2a)-(2m):

-   -   (2a) R¹ is hydrogen, halogen, cyano, nitro, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, heterocyclyl,        aryl, heteroaryl, each optionally substituted with one two or        three R, —R¹⁰, or —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR₂,        —C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R,        —OC(O)OR, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)NR₂, or —N(R)S(O)₂R.    -   (2b) R¹ is hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰,        wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,        —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, or —N(R)S(O)₂R.    -   (2c) R¹ is hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰,        wherein R¹⁰ is —OR¹¹, —N(R¹¹)₂, —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂, or        —N(R¹¹)S(O)₂R¹¹, wherein each R¹¹ is hydrogen or C₁₋₆alkyl.    -   (2d) R¹ is hydrogen, halogen, cyano, C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, —C₁₋₆alkyl-OR¹¹, —OR¹¹,        —N(R¹¹)₂, —S(O)₂N(R¹¹)₂, or —N(R¹¹)S(O)₂R¹¹, wherein each R¹¹ is        hydrogen or C₁₋₆alkyl.    -   (2e) R¹ is fluoro, cyano, methyl, ethyl, isopropyl, t-butyl,        trifluoromethyl, hydroxy, methoxy, isopropoxy, benzyloxy,        cyclopropyl, cyclopentyl, cyclopentenyl, phenyl, amino,        dimethylamino, methylsulfonylamino, aminocarbonyl,        dimethylaminocarbonyl, n-propylaminocarbonyl, aminosulfonyl, or        hydroxymethyl.    -   (2f) R¹ is halogen or C₁₋₆alkyl.    -   (2g) R¹ is halogen or C₁₋₄alkyl.    -   (2h) R¹ is halogen or methyl.    -   (2i) R¹ is fluoro or methyl.    -   (2j) R¹ is fluoro.    -   (2k) R¹ is methyl.    -   (2l) R¹ is hydrogen, halogen, cyano, nitro, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, heterocyclyl,        aryl, heteroaryl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR,        —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂NR₂, —OC(O)R,        —N(R)C(O)R, —OC(O)OR, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)NR₂, or        —N(R)S(O)₂R.    -   (2m) any one of (2a)-(2d) and (2l), where R¹ is not hydrogen.

R² in any of Formulae (I) and (Ia)-(Ir) is Selected from One of theFollowing Groups (3a)-(3m):

-   -   (3a) R² is hydrogen, halogen, cyano, nitro, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, heterocyclyl,        aryl, heteroaryl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR,        —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂NR₂, —OC(O)R,        —N(R)C(O)R, —OC(O)OR, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)NR₂, or        —N(R)S(O)₂R.    -   (3b) R² is hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰,        wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,        —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, or —N(R)S(O)₂R.    -   (3c) R² is hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰,        wherein R¹⁰ is —OR¹¹, —N(R¹¹)₂, —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂, or        —N(R¹¹)S(O)₂R¹¹, wherein each R¹¹ is hydrogen or C₁₋₆alkyl    -   (3d) R² is hydrogen, halogen, cyano, C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, —C₁₋₆alkyl-OR¹¹, —OR¹¹,        —N(R¹¹)₂, —S(O)₂N(R¹¹)₂, or —N(R¹¹)S(O)₂R¹¹, wherein each R¹¹ is        hydrogen or C₁₋₆alkyl.    -   (3e) R² is fluoro, cyano, methyl, ethyl, isopropyl, t-butyl,        trifluoromethyl, hydroxy, methoxy, isopropoxy, benzyloxy,        cyclopropyl, cyclopentyl, cyclopentenyl, phenyl, amino,        dimethylamino, methylsulfonylamino, aminocarbonyl,        dimethylaminocarbonyl, n-propylaminocarbonyl, aminosulfonyl, or        hydroxymethyl.    -   (3f) R² is halogen or C₁₋₆alkyl.    -   (3g) R² is halogen or C₁₋₄alkyl.    -   (3h) R² is halogen or methyl.    -   (3i) R² is fluoro or methyl.    -   (3j) R² is fluoro.    -   (3k) R² is methyl.    -   (3l) R² is hydrogen, halogen, cyano, nitro, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, heterocyclyl,        aryl, heteroaryl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR,        —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂NR₂, —OC(O)R,        —N(R)C(O)R, —OC(O)OR, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)NR₂, or        —N(R)S(O)₂R.    -   (3m) any one of (3a)-(3d) and (3l) where where R² is not        hydrogen.

R¹ and R² in any of Formulae (I) and (Ia)-(Ir) are Selected from One ofthe Following Groups (4a)-(4j):

-   -   (4a) R¹ and R² are each independently hydrogen, halogen, cyano,        nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₃₋₈cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R¹⁰, or        —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R, —C(O)OR,        —C(O)NR₂, —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)NR₂, or —N(R)S(O)₂R.    -   (4b) R¹ and R² are each independently hydrogen, halogen, cyano,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl,        —R¹⁰, or —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R,        —C(O)OR, —C(O)NR₂, —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, or        —N(R)S(O)₂R.    -   (4c) R¹ and R² are each independently hydrogen, halogen, cyano,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,        —R¹⁰, or —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR¹¹, —N(R¹¹)₂,        —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂, or —N(R¹¹)S(O)₂R¹¹, wherein each        R¹¹ is hydrogen or C₁₋₆alkyl.    -   (4d) R¹ and R² are each independently hydrogen, halogen, cyano,        C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, —C₁₋₆alkyl-OR¹¹,        —OR¹¹, —N(R¹¹)₂, —C(O)N(R¹)₂, —S(O)₂N(R¹¹)₂, or —N(R¹¹)S(O)₂R¹¹,        wherein each R¹¹ is hydrogen or C₁₋₆alkyl.    -   (4e) R¹ and R² are each independently hydrogen, fluoro, cyano,        methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, hydroxy,        methoxy, isopropoxy, benzyloxy, cyclopropyl, cyclopentyl,        cyclopentenyl, phenyl, amino, dimethylamino,        methylsulfonylamino, aminocarbonyl, dimethylaminocarbonyl,        n-propylaminocarbonyl, aminosulfonyl, or hydroxymethyl.    -   (4f) R¹ and R² are each independently hydrogen, halogen, or        C₁₋₆alkyl.    -   (4g) R¹ is fluoro and R² is methyl.    -   (4h) any one of (4a)-(4f), where R¹ is not hydrogen.    -   (4i) any one of (4a)-(4f), where R² is not hydrogen.    -   (4j) any one of (4a)-(4f), where neither R¹ nor R² is hydrogen.

R⁵ in any of Formulae (I) and (Ia)-(Ix) is Selected from One of theFollowing Groups (5a)-(5r):

-   -   (5a) R⁵ is hydrogen, halogen, C₁₋₆alkyl, —OR, —NR^(a)R^(a),        —N(R)C(O)R, or —N(R)S(O)₂R.    -   (5b) R⁵ is hydrogen, halogen, C₁₋₆alkyl, —OR⁵⁰, —NR⁵⁰R⁵⁰,        —N(R⁵⁰)C(O)R⁵⁰, or —N(R⁵⁰)S(O)₂R⁵⁰, wherein each R⁵⁰ is        independently hydrogen or C₁₋₆alkyl.    -   (5c) R⁵ is hydrogen, halogen, C₁₋₄alkyl, —OR⁵⁰, —NR⁵⁰R⁵⁰,        —N(R⁵⁰)C(O)R⁵⁰, or —N(R⁵⁰)S(O)₂R⁵⁰, wherein each R⁵⁰ is        independently hydrogen or C₁₋₄alkyl.    -   (5d) R⁵ is hydrogen, fluoro, chloro, methyl, methoxy, ethoxy,        amino, acetylamino, or methylsulfonylamino    -   (5e) R⁵ is fluoro or chloro.    -   (5f) R⁵ is fluoro.    -   (5g) R⁵ is chloro.    -   (5h) R⁵ is methyl.    -   (5i) R⁵ is methoxy or ethoxy.    -   (5j) R⁵ is amino, acetylamino, or methylsulfonylamino    -   (5k) R⁵ is hydrogen.    -   (5l) R⁵ is —NR^(a)R^(a).    -   (5m) R⁵ is —N(R)CO(R).    -   (5n) R⁵ is heteroaryl optionally substituted with one or two        R^(b) or aryl optionally substituted with one or two R^(b).    -   (5o) R⁵ is C₃₋₈cycloalkyl optionally substituted with one or two        R^(b) or heterocyclyl(C₁₋₆alkyl) optionally substituted with one        or two R^(b).    -   (5p) R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —OR, —SR, —NR^(a)R^(a), —OC(O)R, —N(R)C(O)R, or        —N(R)S(O)₂R.    -   (5q) R⁵ is hydrogen, halogen, C₁₋₆alkyl optionally substituted        with 1-3 R^(b), C₁₋₆haloalkyl, C₃₋₈cycloalkyl optionally        substituted with one or two R^(b), heteroaryl optionally        substituted with one or two R^(b), —OR, —SR, —NR^(a)R^(a),        —OC(O)R, —C(O)NR^(a)R^(a), —OC(O)NR^(a)R^(a), —C(O)OR,        —N(R)C(O)R, —N(R)S(O)₂R.    -   (5r) any one of (5a)-(5d), (5p) and (5q), where R⁵ is not        hydrogen.

R⁶ in any of Formulae (I) and (Ia)-(Ix) is Selected from One of theFollowing Groups (6a)-(6n):

-   -   (6a) R⁶ is hydrogen, halogen, C₁₋₆alkyl, —OR, —NR^(a)R^(a),        —N(R)C(O)R, or —N(R)S(O)₂R.    -   (6b) R⁶ is hydrogen, halogen, C₁₋₆alkyl, —OR⁶⁰, —NR⁶⁰R⁶⁰,        —N(R⁶⁰)C(O)R⁶⁰, or —N(R⁶⁰)S(O)₂R⁶⁰, wherein each R⁶⁰ is        independently hydrogen or C₁₋₆alkyl.    -   (6c) R⁶ is hydrogen, halogen, C₁₋₄alkyl, —OR⁶⁰, —NR⁶⁰R⁶⁰,        —N(R⁶⁰)C(O)R⁶⁰, or —N(R⁶⁰)S(O)₂R⁶⁰, wherein each R⁶⁰ is        independently hydrogen or C₁₋₄alkyl.    -   (6d) R⁶ is hydrogen, fluoro, chloro, methyl, methoxy, ethoxy,        amino, acetylamino, or methylsulfonylamino    -   (6e) R⁶ is fluoro or chloro.    -   (6f) R⁶ is fluoro.    -   (6g) R⁶ is chloro.    -   (6h) R⁶ is methyl.    -   (6i) R⁶ is methoxy or ethoxy.    -   (6j) R⁶ is amino, acetylamino, or methylsulfonylamino    -   (6k) R⁶ is hydrogen.    -   (6l) R⁶ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —OR, —SR, —NR^(a)R^(a), —OC(O)R, —N(R)C(O)R, or        —N(R)S(O)₂R.    -   (6m) R⁶ is hydrogen, halogen, C₁₋₆alkyl optionally substituted        with 1-3 R^(b), C₁₋₆haloalkyl, C₃₋₈cycloalkyl optionally        substituted with one or two R^(b), heteroaryl optionally        substituted with one or two R^(b), —OR, —SR, —NR^(a)R^(a),        —OC(O)R, —C(O)NR^(a)R^(a), —OC(O)NR^(a)R^(a), —C(O)OR,        —N(R)C(O)R, —N(R)S(O)₂R.    -   (6n) any one of (6a)-(6d), (6l) and (6m), where R⁶ is not        hydrogen.

R⁵ and R⁶ in any of Formulae (I) and (Ia)-(Ix) are Selected from One ofthe Following Groups (7a)-(7u):

-   -   (7a) R⁵ and R⁶ are each independently hydrogen, halogen,        C₁₋₆alkyl, —OR, —NR^(a)R^(a), —N(R)C(O)R, or —N(R)S(O)₂R.    -   (7b) one of R⁵ and R⁶ is hydrogen, and the other is halogen,        C₁₋₆alkyl, —OR, —NR^(a)R^(a), —N(R)C(O)R, or —N(R)S(O)₂R.    -   (7c) R⁵ and R⁶ are each independently hydrogen, halogen,        C₁₋₆alkyl, —OR⁷, —NR⁷R⁷, —N(R⁷)C(O)R⁷, or —N(R⁷)S(O)₂R⁷, wherein        each R⁷ is independently hydrogen or C₁₋₆alkyl.    -   (7d) one of R⁵ and R⁶ is hydrogen, and the other is halogen,        C₁₋₆alkyl, —OR⁷, —NR⁷R⁷, —N(R⁷)C(O)R⁷, or —N(R⁷)S(O)₂R⁷, wherein        each R⁷ is independently hydrogen or C₁₋₆alkyl.    -   (7e) R⁵ and R⁶ are each independently hydrogen, halogen,        C₁₋₄alkyl, —OR⁷, —NR⁷R⁷, —N(R⁷)C(O)R⁷, or —N(R⁷)S(O)₂R⁷, wherein        each R⁷ is independently hydrogen or C₁₋₄alkyl.    -   (7f) one of R⁵ and R⁶ is hydrogen, and the other is halogen,        C₁₋₄alkyl, —OR⁷, —NR⁷R⁷, —N(R⁷)C(O)R⁷, or —N(R⁷)S(O)₂R⁷, wherein        each R⁷ is independently hydrogen or C₁₋₄alkyl.    -   (7g) R⁵ and R⁶ are each independently hydrogen, fluoro, chloro,        methyl, methoxy, ethoxy, amino, acetylamino, or        methylsulfonylamino    -   (7h) one of R⁵ and R⁶ is hydrogen, and the other is fluoro,        chloro, methyl, methoxy, ethoxy, amino, acetylamino, or        methylsulfonylamino.    -   (7i) any one of (7a)-(7h), where one of R⁵ and R⁶ is not        hydrogen.    -   (7j) R⁵ and R⁶ are each hydrogen.    -   (7k) one of R⁵ and R⁶ is hydrogen, and the other is fluoro, or        chloro.    -   (7l) one of R⁵ and R⁶ is hydrogen, and the other is methyl.    -   (7m) one of R⁵ and R⁶ is hydrogen, and the other is methoxy or        ethoxy.    -   (7n) one of R⁵ and R⁶ is hydrogen, and the other is amino,        acetylamino, or methylsulfonylamino    -   (7o) one of R⁵ and R⁶ is hydrogen, and the other is amino.    -   (7p) one of R⁵ and R⁶ is hydrogen, and the other is acetylamino    -   (7q) one of R⁵ and R⁶ is hydrogen, and the other is        methylsulfonylamino    -   (7r) R⁵ and R⁶ are each independently hydrogen, halogen,        C₁₋₆alkyl optionally substituted with 1-3 R^(b), C₁₋₆haloalkyl,        C₃₋₈cycloalkyl optionally substituted with one or two R^(b),        heteroaryl optionally substituted with one or two R^(b), —OR,        —SR, —NR^(a)R^(a), —OC(O)R, —C(O)NR^(a)R^(a), —OC(O)NR^(a)R^(a),        —C(O)OR, —N(R)C(O)R, —N(R)S(O)₂R, or R⁵ and R⁶ are optionally        taken together with the atoms to which they are attached to form        a 5- or 6-membered ring optionally including 1-3 additional        heteroatoms selected from O, N and S and optionally substituted        with 1-4 R^(b).    -   (7s) R⁵ and R⁶ are taken together with the atoms to which they        are attached to form a 5- or 6-membered ring optionally        including 1-3 additional heteroatoms selected from O, N and S        and optionally substituted with 1-4 R^(b).    -   (7t) R⁵ and R⁶ are each independently hydrogen, halogen,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —OR, —SR,        —NR^(a)R^(a), —OC(O)R, —N(R)C(O)R, or —N(R)S(O)₂R.    -   (7u) any one of (7r) and (7t), where one of R⁵ and R⁶ is not        hydrogen.

Z in any of Formulae (I) and (Ia)-(Ix) is Selected from One of theFollowing Groups (8a)-(8tt):

-   -   (8a) Z is a fused bicyclic ring of the formula,

-   -    wherein ring A is a phenyl or pyridyl ring; and ring B is a 5-        or 6-membered heterocyclyl or 5- or 6-membered heteroaryl,        wherein Z is optionally substituted as in formula (I).    -   (8b) Z is as in (8a), wherein ring B is a 5- or 6-membered        heterocyclyl.    -   (8c) Z is as in (8a), wherein ring B is a 5-membered        heterocyclyl.    -   (8d) Z is as in (8a), wherein ring B is a 6-membered        heterocyclyl.    -   (8e) Z is as in (8a), wherein ring B is a 5- or 6-membered        heteroaryl.    -   (8f) Z is as in (8a), wherein ring B is a 5-membered heteroaryl.    -   (8g) Z is as in (8a), wherein ring B is a thienyl, pyrrolyl,        furanyl, imidazolyl, pyrazolyl, thiazolyl, or oxazolyl ring.    -   (8h) Z is as in (8a), wherein ring B is a 6-membered heteroaryl.    -   (8i) Z is as in (8a), wherein ring B is a pyridyl, pyrimidinyl,        or pyrazinyl ring.    -   (8j) Z is as in any one of (8a)-(8i), wherein ring A is a phenyl        ring.    -   (8k) Z is as in any one of (8a)-(8i), wherein ring A is a        pyridyl ring.    -   (8l) Z is of the formula,

-   -   -   wherein each is optionally substituted by one or two groups            that are each independently halogen, C₁₋₆alkyl,            C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl,            heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),            heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl),            heteroaryl(C₁₋₆alkyl), —R^(Z), or —C₁₋₆alkyl-R^(Z), wherein            the C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,            C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),            aryl(C₁₋₆alkyl), and heteroaryl(C₁₋₆alkyl) are each            optionally substituted by one to four groups that are each            independently C₁₋₆alkyl or R^(Z).

    -   (8m) Z is of the formula,

-   -   -   wherein each is optionally substituted by one or two groups            that are each independently halogen, C₁₋₆alkyl,            C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl,            heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),            heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl),            heteroaryl(C₁₋₆alkyl), —R^(Z), or —C₁₋₆alkyl-R^(Z), wherein            the C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,            C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),            aryl(C₁₋₆alkyl), and heteroaryl(C₁₋₆alkyl) are each            optionally substituted by one to four groups that are each            independently C₁₋₆alkyl or R^(Z).

    -   (8n) Z is of the formula,

-   -   -   wherein R^(Z1) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,            C₃₋₈cycloalkyl or —C₁₋₆alkyl-R^(Z); and        -   R^(Z2) is hydrogen, halogen, C₁₋₆haloalkyl, C₃₋₈cycloalkyl            or C₁₋₆alkyl, wherein the C₃₋₈cycloalkyl for R^(Z1) and            R^(Z2) are optionally substituted with one or two halogen,            C₁₋₆alkyl, or R^(Z).

    -   (8o) Z is of the formula,

-   -   -   wherein        -   Q is —O—, —S—, or —N(R^(Z1))—; and        -   R^(Z1) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, or            —C₁₋₆alkyl-R^(Z); and        -   R^(Z2) is hydrogen, halogen, or C₁₋₆alkyl.

    -   (8p) As in (8o), where Z is of the formula,

-   -   (8q) As in (8o), where Z is of the formula,

-   -   (8r) As in (8o), where Z is of the formula,

-   -   (8s) As in (8o), where Z is of the formula,

-   -   (8t) As in (8o), where Z is of the formula,

-   -   (8u) As in (8o), where Z is of the formula,

-   -   (8v) As in (8o), where Z is of the formula,

-   -   (8w) As in (8o), where Z is of the formula,

-   -   (8x) As in (8o), where Z is of the formula,

-   -   (8y) As in (8o), where Z is of the formula,

-   -   (8z) As in any one of (8n), (8r)-(8t), and (8y), where R^(Z1) is        hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl,        heterocyclyl, aryl, heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),        heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), heteroaryl(C₁₋₆alkyl),        —R^(Z3), —C₁₋₆alkyl-R^(Z3), or —C₁₋₆alkyl-R^(Z4), wherein R^(Z3)        is —C(O)R, —C(O)OR, —C(O)NR₂, or —S(O)₂NR₂; and R^(Z4) is —OR,        —SR, —NR₂, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)NR₂, —N(R)S(O)₂R, or —OP(O)(OR)₂.    -   (8aa) As in any one of (8n), (8r)-(8t), and (8y), where R^(Z1)        is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        heterocyclyl, aryl, heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),        heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), heteroaryl(C₁₋₆alkyl),        or —C₁₋₆alkyl-R^(Z4), wherein R^(Z3) is —C(O)R^(Z6),        —C(O)OR^(Z6), —C(O)NR^(Z6) ₂, or —S(O)₂NR^(Z5) ₂; and R^(Z4) is        —OR^(Z5), —SR^(Z5), —NR^(Z5) ₂, —OC(O)R^(Z5),        —N(R^(Z5))C(O)R^(Z5), —OC(O)OR^(Z5), —OC(O)NR^(Z5) ₂,        —N(R^(Z5))C(O)OR^(Z5), —N(R^(Z5))C(O)NR^(Z5) ₂,        —N(R^(Z5))S(O)₂R^(Z5), or —OP(O)(OR^(Z5))₂, and wherein each        R^(Z5) is independently hydrogen or C₁₋₆alkyl; and each R^(Z6)        is independently hydrogen or C₁₋₆alkyl,        C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),        aryl(C₁₋₆alkyl), or heteroaryl(C₁₋₆alkyl), each optionally        substituted by one or two groups that are each independently        —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂,        —S(O)₂N(R⁰)₂, —OC(O)R⁰, —N(R⁰)C(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂,        —N(R⁰)C(O)OR⁰, —N(R⁰)C(O)N(R⁰)₂, or —N(R⁰)S(O)₂R⁰, wherein each        R⁰ is independently hydrogen or C₁₋₆alkyl.    -   (8bb) As in any one of (8n), (8r)-(8t), and (8y), where R^(Z1)        is hydrogen, C₁₋₆alkyl, heterocyclyl, heterocyclyl(C₁₋₆alkyl),        —C₁₋₆alkyl-R^(Z4), or —C(O)OR^(Z6), wherein R^(Z4) is —OR^(Z5),        —SR^(Z5), —NR^(Z5) ₂, —OC(O)R^(Z5), N(R^(Z5))C(O)—R^(Z5),        —OC(O)OR^(Z5), —OC(O)NR^(Z5) ₂, —N(R^(Z5))C(O)OR^(Z5),        —N(R^(Z5))C(O)NR^(Z5) ₂, —N(R^(Z5))S(O)₂R^(Z5), or        —OP(O)(OR^(Z5))₂, wherein the heterocyclyl and        heterocyclyl(C₁₋₆alkyl) are each optionally substituted by one        or two groups that are each independently halogen or C₁₋₆alkyl;        and wherein each R^(Z5) is independently hydrogen or C₁₋₆alkyl;        and each R^(Z6) is independently hydrogen or C₁₋₆alkyl,        C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),        aryl(C₁₋₆alkyl), or heteroaryl(C₁₋₆alkyl), each optionally        substituted by —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, or        —C(O)N(R⁰)₂, wherein each R⁰ is independently hydrogen or        C₁₋₆alkyl.    -   (8cc) As in any one of (8n), (8r)-(8t), and (8y), where R^(Z1)        is hydrogen, C₁₋₆alkyl, heterocyclyl, heterocyclyl(C₁₋₆alkyl),        —C₁₋₆alkyl-OR^(Z5), —C₁₋₆alkyl-OP(O)(OR^(Z5))₂, or —C(O)OR^(Z6),        wherein the heterocyclyl and heterocyclyl(C₁₋₆alkyl) are each        optionally substituted by one or two C₁₋₆alkyl groups; and        wherein each R^(Z5) is independently hydrogen or C₁₋₆alkyl; each        R^(Z6) is independently hydrogen or C₁₋₆alkyl or        heteroaryl(C₁₋₆alkyl), each optionally substituted by —OR⁰, or        —N(R⁰)₂, wherein each R⁰ is independently hydrogen or C₁₋₆alkyl.    -   (8dd) As in any one of (8n), (8r)-(8t), and (8y), where R^(Z1)        is hydrogen, methyl, ethyl, isopropyl, 2-(morpholin-4-yl)ethyl,        2-(4-methylpiperazin-1-yl)ethyl, 3-hydroxypropyl,        3-ethoxypropyl, 4-tetrahydropyranyl, N-methylpiperidin-4-yl,        —CH₂—OP(O)(OH)₂, or 3-(indol-3-yl)-2-aminopropyloxycarbonyl.    -   (8ee) As in any one of (8n)-(8dd), where R^(Z2) is hydrogen or        halogen.    -   (8ff) As in any one of (8n)-(8dd), where R^(Z2) is hydrogen or        C₁₋₆alkyl.    -   (8gg) As in any one of (8n)-(8dd), where R^(Z2) is hydrogen or        methyl.    -   (8hh) As in any one of (8n)-(8dd), where R^(Z2) is hydrogen.    -   (8ii) Z is halophenyl (e.g., 4-halophenyl).    -   (8jj) Z is dihalophenyl.    -   (8kk) Z is fluorophenyl.    -   (8ll) Z is 4-fluorophenyl.    -   (8 mm) Z is

-   -   (8nn) Z is

-   -    Z is

-   -   (8oo) In any one of (8nn) and (8oo), independently is for each        occurrence hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl or        —C₁₋₆alkyl-R^(Z), wherein the C₃₋₈cycloalkyl are optionally        substituted by one or two halogen, C₁₋₆alkyl, or —R^(Z).    -   (8pp) In any one of (8nn)-(8pp), R^(Z2) independently is for        each occurrence hydrogen, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —R^(Z), or —C₁₋₆alkyl-R^(Z), wherein the        C₃₋₈cycloalkyl are optionally substituted by one or two halogen,        C₁₋₆alkyl, or —R^(Z).    -   (8qq) Z is of the formula,

-   -    wherein each is optionally substituted by one or two groups        that are each independently halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,        C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),        aryl(C₁₋₆alkyl), heteroaryl(C₁₋₆alkyl), —R^(Z), or        —C₁₋₆alkyl-R^(Z), wherein the C₃₋₈cycloalkyl, heterocyclyl,        aryl, heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),        heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), and        heteroaryl(C₁₋₆alkyl) are each optionally substituted by one to        four groups that are each independently C₁₋₆alkyl or R^(Z).    -   (8rr) Z is of the formula,

-   -   -   wherein R^(Z1) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, or            —C₁₋₆alkyl-R^(Z); and R^(Z2) is hydrogen, halogen, or            C₁₋₆alkyl.

    -   (8ss) Z is pyridinyl.

    -   (8tt) Z is pyrimidinyl, optionally substituted by one or two        groups that are each independently halogen, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,        C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),        aryl(C₁₋₆alkyl), heteroaryl(C₁₋₆alkyl), —R^(Z), or        —C₁₋₆alkyl-R^(Z), wherein the C₃₋₈cycloalkyl, heterocyclyl,        aryl, heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),        heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), and        heteroaryl(C₁₋₆alkyl) are each optionally substituted by one or        two groups that are each independently halogen, C₁₋₆alkyl, or        R^(Z); and R^(Z) is cyano, —CF₃, —OR, —SR, —NR^(a)R^(a), —C(O)R,        —C(O)OR, —C(O)NR^(a)R^(a), —S(O)₂NR^(a)R^(a), —S(O)₂R⁰, —OC(O)R,        —N(R)C(O)R, —OC(O)OR, —OC(O)NR^(a)R^(a), —N(R)C(O)OR,        —N(R)C(O)NR^(a)R^(a), —N(R)S(O)₂R, or —OP(O)(OR)₂.

In in any of Formulae (I) and (Ia)-(If) is Selected from One of theFollowing Definitions (9a)-(9c):

-   -   (9a) n is 1.    -   (9b) n is 1, 2 or 3.    -   (9c) n is 1 or 2.

The compounds of formulae (I) and (Ia)-(Ix) described above are usefulas kinase inhibitors and/or inhibitors of cytokine signaling. Exemplarykinases inhibited by the presently disclosed compounds formulae I and(Ia)-(Ix) include, without limitation, ACVR1; ACVR1B (ALK-4); ACVR1C;ACVR2A; ACVR2B; ACVRL1; BMPR1A; BMPR1B; BMPR2; TGFBR1 (ALK-5), PI3K andMAP4K4 (HGK). Exemplary cytokines, the signaling of which is inhibitedby the present compounds of formulae (I), include, without limitation,TGF-β superfamily, including TGF-β1 and GDF-8. In one aspect the presentcompounds are selective for one or more kinase and/or cytokine signalingpathway. For example, exemplary compounds inhibit TGF-β1 signaling,GDF-8 signaling, or both. In one aspect the present compounds inhibitGDF-8 signaling preferentially to TGF-β1 signaling, such that GDF8signaling is inhibited at least about 1.5-fold more potently or fromabout 1.1-fold to about 25-fold more potently. In one embodiment certaincompounds inhibit GDF8 signaling at least about 5-fold more potently,such as from about 8-fold to about 50-fold, or at least about 10-foldmore potently, such as from about 15-fold to about 300-fold morepotently.

Exemplary compounds of formulae I and (Ia-Ix) (e.g., Compounds 63, 389,448, 456, 460, 494 and 818) inhibit MAP4K4 with an IC50 of less thanabout 500 nM. Such compounds are particularly useful in muscledisorders, such as cachexia and sarcopenia as MAP4K4 acts as asuppressor of skeletal muscle differentiation. See, Wang M, Amano S U,Flach R J, Chawla A, Aouadi M, Czech P. Molecular and cellular biology.2013 February; 33(4): 678-87.

In particular the present compounds can be use to treat disorders, suchas pulmonary hypertension, chronic renal disease, acute renal disease,wound healing, arthritis, osteoporosis, kidney disease, congestive heartfailure, ulcers, ocular disorders, corneal wounds, diabetic nephropathy,impaired neurological function, Alzheimer's disease, atherosclerosis,peritoneal and sub-dermal adhesion, kidney fibrosis, lung fibrosis,including idiopathic pulmonary fibrosis, and liver fibrosis, hepatitisB, hepatitis C, alcohol-induced hepatitis, cancer, haemochromatosis,primary biliary cirrhosis, restenosis, retroperitoneal fibrosis,mesenteric fibrosis, endometriosis, keloids, cancer, abnormal bonefunction, inflammatory disorders, scarring and photaging of the skin.

Particular proliferative diseases that can be treated with the presentcompounds include those selected from a benign or malignant tumor,carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast,stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas,lung, vagina or thyroid, sarcoma, glioblastomas, multiple myeloma orgastrointestinal cancer, especially colon carcinoma or colorectaladenoma or a tumor of the neck and head, an epidermalhyperproliferation, melanoma, psoriasis, prostate hyperplasia, aneoplasia, a neoplasia of epithelial character, leukemias and lymphomas,a mammary carcinoma or a leukemia. Other diseases include Cowdensyndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome, ordiseases in which the PI3K/PKB pathway is aberrantly activated.

The compounds of Formula (I) described herein also include isotopicallylabeled compounds where one or more atoms have an atomic mass differentfrom the atomic mass conventionally found in nature. Examples ofisotopes that may be incorporated into the compounds disclosed hereininclude, but are not limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,¹⁸F etc. Thus, the disclosed compounds may be enriched in one or more ofthese isotopes relative to the natural abundance of such isotope. As isknown to those of skill in the art, such isotopically enriched compoundsare useful for a variety of purposes. For example, substitution withheavier isotopes such as deuterium (²H) may afford certain therapeuticadvantages that result from greater metabolic stability. Substitutionwith positron emitting isotopes, such as 18F can be useful in PositronEmission Tomography (PET) studies. By way of example, deuterium (²H) hasa natural abundance of about 0.015%. Accordingly, for approximatelyevery 6,500 hydrogen atoms occurring in nature, there is one deuteriumatom. Specifically contemplated herein are compounds enriched indeuterium at one or more positions. Thus, deuterium containing compoundsof the disclosure have deuterium at one or more positions (as the casemay be) in an abundance of greater than 0.015%.

Particular embodiments of this aspect of the disclosure includecompounds of any one of the Formula (I), each as defined in each of thefollowing rows, wherein each entry is a group number as defined above(e.g., (1b) refers to X is N), and a dash “—” indicates that thevariable is as defined for formula (I) or defined according to any oneof the applicable variable definitions (1a)-(8ll) [e.g., when X is adash, it can be either as defined for Formula (I) or any one ofdefinitions (1a)-(1b)]:

Formula (I) R¹ & R² R⁵ & R⁶ Z (Id) (4a) (7a) (8a) (Id) (4a) (7a) (8n)(Id) (4a) (7a) (8rr) (Id) (4a) (7a) (8o) (Id) (4a) (7g) (8a) (Id) (4a)(7g) (8n) (Id) (4a) (7g) (8rr) (Id) (4a) (7g) (8o) (Id) (4a) (7i) (8a)(Id) (4a) (7i) (8n) (Id) (4a) (7i) (8rr) (Id) (4a) (7i) (8o) (Id) (4d)(7a) (8a) (Id) (4d) (7a) (8n) (Id) (4d) (7a) (8rr) (Id) (4d) (7a) (8o)(Id) (4d) (7g) (8a) (Id) (4d) (7g) (8n) (Id) (4d) (7g) (8rr) (Id) (4d)(7g) (8o) (Id) (4d) (7i) (8a) (Id) (4d) (7i) (8n) (Id) (4d) (7i) (8rr)(Id) (4d) (7i) (8o) (Id) (4e) (7a) (8a) (Id) (4e) (7a) (8n) (Id) (4e)(7a) (8rr) (Id) (4e) (7a) (8o) (Id) (4e) (7g) (8a) (Id) (4e) (7g) (8n)(Id) (4e) (7g) (8rr) (Id) (4e) (7g) (8o) (Id) (4e) (7i) (8a) (Id) (4e)(7i) (8n) (Id) (4e) (7i) (8rr) (Id) (4e) (7i) (8o) (Id) (4f) (7a) (8a)(Id) (4f) (7a) (8n) (Id) (4f) (7a) (8rr) (Id) (4f) (7a) (8o) (Id) (4f)(7g) (8a) (Id) (4f) (7g) (8n) (Id) (4f) (7g) (8rr) (Id) (4f) (7g) (8o)(Id) (4f) (7i) (8a) (Id) (4f) (7i) (8n) (Id) (4f) (7i) (8rr) (Id) (4f)(7i) (8o) (Id) (4g) (7a) (8a) (Id) (4g) (7a) (8n) (Id) (4g) (7a) (8rr)(Id) (4g) (7a) (8o) (Id) (4g) (7g) (8a) (Id) (4g) (7g) (8n) (Id) (4g)(7g) (8rr) (Id) (4g) (7g) (8o) (Id) (4g) (7i) (8a) (Id) (4g) (7i) (8n)(Id) (4g) (7i) (8rr) (Id) (4g) (7i) (8o) (Id) (2j), (3k) (7a) (8a) (Id)(2j), (3k) (7a) (8n) (Id) (2j), (3k) (7a) (8rr) (Id) (2j), (3k) (7a)(8o) (Id) (2j), (3k) (7g) (8a) (Id) (2j), (3k) (7g) (8n) (Id) (2j), (3k)(7g) (8rr) (Id) (2j), (3k) (7g) (8o) (Id) (2j), (3k) (7i) (8a) (Id)(2j), (3k) (7i) (8n) (Id) (2j), (3k) (7i) (8rr) (Id) (2j), (3k) (7i)(8o) (Ie) (4a) (7a) (8a) (Ie) (4a) (7a) (8n) (Ie) (4a) (7a) (8rr) (Ie)(4a) (7a) (8o) (Ie) (4a) (7g) (8a) (Ie) (4a) (7g) (8n) (Ie) (4a) (7g)(8rr) (Ie) (4a) (7g) (8o) (Ie) (4a) (7i) (8a) (Ie) (4a) (7i) (8n) (Ie)(4a) (7i) (8rr) (Ie) (4a) (7i) (8o) (Ie) (4d) (7a) (8a) (Ie) (4d) (7a)(8n) (Ie) (4d) (7a) (8rr) (Ie) (4d) (7a) (8o) (Ie) (4d) (7g) (8a) (Ie)(4d) (7g) (8n) (Ie) (4d) (7g) (8rr) (Ie) (4d) (7g) (8o) (Ie) (4d) (7i)(8a) (Ie) (4d) (7i) (8n) (Ie) (4d) (7i) (8rr) (Ie) (4d) (7i) (8o) (Ie)(4e) (7a) (8a) (Ie) (4e) (7a) (8n) (Ie) (4e) (7a) (8rr) (Ie) (4e) (7a)(8o) (Ie) (4e) (7g) (8a) (Ie) (4e) (7g) (8n) (Ie) (4e) (7g) (8n) (Ie)(4e) (7g) (8o) (Ie) (4e) (7i) (8a) (Ie) (4e) (7i) (8n) (Ie) (4e) (7g)(8rr) (Ie) (4e) (7i) (8o) (Ie) (4f) (7a) (8a) (Ie) (4f) (7a) (8n) (Ie)(4f) (7a) (8rr) (Ie) (4f) (7a) (8o) (Ie) (4f) (7g) (8a) (Ie) (4f) (7g)(8n) (Ie) (4f) (7g) (8rr) (Ie) (4f) (7g) (8o) (Ie) (4f) (7i) (8a) (Ie)(4f) (7i) (8n) (Ie) (4f) (7i) (8rr) (Ie) (4f) (7i) (8o) (Ie) (4g) (7a)(8a) (Ie) (4g) (7a) (8n) (Ie) (4g) (7a) (8rr) (Ie) (4g) (7a) (8o) (Ie)(4g) (7g) (8a) (Ie) (4g) (7g) (8n) (Ie) (4g) (7g) (8rr) (Ie) (4g) (7g)(8o) (Ie) (4g) (7i) (8a) (Ie) (4g) (7i) (8n) (Ie) (4g) (7i) (8rr) (Ie)(4g) (7i) (8o) (Ie) (2j), (3k) (7a) (8a) (Ie) (2j), (3k) (7a) (8n) (Ie)(2j), (3k) (7a) (8rr) (Ie) (2j), (3k) (7a) (8o) (Ie) (2j), (3k) (7g)(8a) (Ie) (2j), (3k) (7g) (8n) (Ie) (2j), (3k) (7g) (8rr) (Ie) (2j),(3k) (7g) (8o) (Ie) (2j), (3k) (7i) (8a) (Ie) (2j), (3k) (7i) (8n) (Ie)(2j), (3k) (7i) (8rr) (Ie) (2j), (3k) (7i) (8o) (If) (4a) — (8a) (If)(4a) — (8n) (If) (4a) — (8rr) (If) (4a) — (8o) (If) (4d) — (8a) (If)(4d) — (8n) (If) (4d) — (8rr) (If) (4d) — (8o) (If) (4e) — (8a) (If)(4e) — (8n) (If) (4e) — (8rr) (If) (4e) — (8o) (If) (4f) — (8a) (If)(4f) — (8n) (If) (4f) — (8rr) (If) (4f) — (8o) (If) (4g) — (8a) (If)(4g) — (8n) (If) (4g) — (8rr) (If) (4g) — (8o) (If) (2j), (3k) — (8a)(If) (2j), (3k) — (8n) (If) (2j), (3k) — (8rr) (If) (2j), (3k) — (8o)(Ir) (4a) — (8a) (Ir) (4a) — (8n) (Ir) (4a) — (8rr) (Ir) (4a) — (8o)(Ir) (4d) — (8a) (Ir) (4d) — (8n) (Ir) (4d) — (8rr) (Ir) (4d) — (8o)(Ir) (4e) — (8a) (Ir) (4e) — (8n) (Ir) (4e) — (8rr) (Ir) (4e) — (8o)(Ir) (4f) — (8a) (Ir) (4f) — (8n) (Ir) (4f) — (8rr) (Ir) (4f) — (8o)(Ir) (4g) — (8a) (Ir) (4g) — (8n) (Ir) (4g) — (8rr) (Ir) (4g) — (8o)(Ir) (2j), (3k) — (8a) (Ir) (2j), (3k) — (8n) (Ir) (2j), (3k) — (8rr)(Ir) (2j), (3k) — (8o)

In certain such embodiments, n is 1.

In one particular embodiment, the compound of formula (I) is accordingto the formula,

-   -   or pharmaceutically acceptable salts thereof, wherein    -   R¹ and R² are each independently hydrogen, halogen, cyano,        nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₃₋₈cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R¹⁰, or        —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R, —C(O)OR,        —C(O)NR₂, —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —OR, —SR, —NR₂, —OC(O)R,        —N(R)C(O)R, or —N(R)S(O)₂R;    -   R^(Z1) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        heterocyclyl, aryl, heteroaryl, C₃₋₈ cycloalkyl(C₁₋₆alkyl),        heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), heteroaryl(C₁₋₆alkyl),        —R^(Z3), —C₁₋₆alkyl-R^(Z3), or —C₁₋₆alkyl-R^(Z4), wherein the        C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,        C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),        aryl(C₁₋₆alkyl), and heteroaryl(C₁₋₆alkyl) are each optionally        substituted by one or two groups that are each independently        halogen, C₁₋₆alkyl, —R^(Z3), or —R^(Z4), wherein        -   R^(Z3) is —C(O)R, —C(O)OR, —C(O)NR₂, or —S(O)₂NR₂; and        -   R^(Z4) is —OR, —SR, —NR₂, —OC(O)R, —N(R)C(O)R, —OC(O)OR,            —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)NR₂, —N(R)S(O)₂R, or            —OP(O)(OR)₂;    -   R^(Z2) is hydrogen, halogen, or C₁₋₆alkyl;    -   and each R is independently hydrogen or C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,        C₃₋₈ cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),        aryl(C₁₋₆alkyl), or heteroaryl(C₁₋₆alkyl), each optionally        substituted by one or two groups that are each independently        —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂,        —S(O)₂N(R⁰)₂, —OC(O)R⁰, —N(R⁰)C(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂,        —N(R⁰)C(O)OR⁰, —N(R⁰)C(O)N(R⁰)₂, or —N(R⁰)S(O)₂R⁰, wherein each        R⁰ is independently hydrogen or C₁₋₆alkyl.

The disclosure further comprises subgenera of formula (II) in which thesubstituents are selected as any and all combinations of one or more ofR¹, R², R⁵, R⁶, R^(Z1), and R^(Z2) as defined herein, including withoutlimitation, the following:

R¹ is Selected from One of the Following Groups (9a)-(9k):

-   -   (9a) R¹ is hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰,        wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,        —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, or —N(R)S(O)₂R.    -   (9b) R¹ is hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰,        wherein R¹⁰ is —OR¹¹, —C(O)N(R¹¹), —S(O)₂N(R¹¹)₂, or        —N(R¹¹)S(O)₂R¹¹, wherein each R¹¹ is hydrogen or C₁₋₆alkyl.    -   (9c) R¹ is hydrogen, halogen, cyano, C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, —C₁₋₆alkyl-OR¹¹, —OR¹¹,        —N(R¹¹)₂, —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂, or —N(R¹¹)S(O)₂R¹¹,        wherein each R¹¹ is hydrogen or C₁₋₆alkyl.    -   (9d) R¹ is fluoro, cyano, methyl, ethyl, isopropyl, t-butyl,        trifluoromethyl, hydroxy, methoxy, isopropoxy, benzyloxy,        cyclopropyl, cyclopentyl, cyclopentenyl, phenyl, amino,        dimethylamino, methylsulfonylamino, aminocarbonyl,        dimethylaminocarbonyl, n-propylaminocarbonyl, aminosulfonyl, or        hydroxymethyl.    -   (9e) R¹ is halogen or C₁₋₆alkyl.    -   (9t) R¹ is halogen or C₁₋₄alkyl.    -   (9g) R¹ is halogen or methyl.    -   (9h) R¹ is fluoro or methyl.    -   (9i) R¹ is fluoro.    -   (9j) R¹ is methyl.    -   (9k) any one of (9a)-(9c), where R¹ is not hydrogen.

R² is Selected from One of the Following Groups (10a)-(10k):

-   -   (10a) R² is hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰,        wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,        —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, or —N(R)S(O)₂R.    -   (10b) R² is hydrogen, halogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰,        wherein R¹⁰ is —OR¹¹, — C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂, or        —N(R¹¹)S(O)₂R¹¹, wherein each R¹¹ is hydrogen or C₁₋₆alkyl.    -   (10c) R² is hydrogen, halogen, cyano, C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, —C₁₋₆alkyl-OR¹¹, —OR¹¹,        —N(R¹¹)₂, —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂, or —N(R¹¹)S(O)₂R¹¹,        wherein each R¹¹ is hydrogen or C₁₋₆alkyl.    -   (10d) R² is fluoro, cyano, methyl, ethyl, isopropyl, t-butyl,        trifluoromethyl, hydroxy, methoxy, isopropoxy, benzyloxy,        cyclopropyl, cyclopentyl, cyclopentenyl, phenyl, amino,        dimethylamino, methylsulfonylamino, aminocarbonyl,        dimethylaminocarbonyl, n-propylaminocarbonyl, aminosulfonyl, or        hydroxymethyl.    -   (10e) R² is halogen or C₁₋₆alkyl.    -   (10f) R² is halogen or C₁₋₄alkyl.    -   (10g) R² is halogen or methyl.    -   (10h) R² is fluoro or methyl.    -   (10i) R² is fluoro.    -   (10j) R² is methyl.    -   (10k) As in any of (10a)-(10c), in which R² is not hydrogen.

R¹ and R² are Selected from One of the Following Groups (11a)-(11i):

-   -   (11a) R¹ and R² are each independently hydrogen, halogen, cyano,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,        —R¹⁰, or —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R,        —C(O)OR, —C(O)NR₂, —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, or        —N(R)S(O)₂R.    -   (11b) R¹ and R² are each independently hydrogen, halogen, cyano,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,        —R¹⁰, or —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR¹¹, —N(R¹¹)₂,        —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂, or —N(R¹¹)S(O)₂R¹¹), wherein each        R¹¹ is hydrogen or C₁₋₆alkyl.    -   (11c) R¹ and R² are each independently hydrogen, halogen, cyano,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,        —C₁₋₆alkyl-OR¹¹, —OR¹¹, —N(R¹¹)₂, —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂,        or —N(R¹¹)S(O)₂R¹¹, wherein each R¹¹ is hydrogen or C₁₋₆alkyl.    -   (11d) R¹ and R² are each independently hydrogen, fluoro, cyano,        methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, hydroxy,        methoxy, isopropoxy, benzyloxy, cyclopropyl, cyclopentyl,        cyclopentenyl, phenyl, amino, dimethylamino,        methylsulfonylamino, aminocarbonyl, dimethylaminocarbonyl,        n-propylaminocarbonyl, aminosulfonyl, or hydroxymethyl.    -   (11e) R¹ and R² are each independently hydrogen, halogen, or        C₁₋₆alkyl.    -   (11f) R¹ is fluoro and R² is methyl.    -   (11g) any one of (11a)-(11e), where R¹ is not hydrogen.    -   (11h) any one of (11a)-(11e), where R² is not hydrogen.    -   (11i) any one of (11a)-(11e), where neither R¹ nor R² is        hydrogen.

R⁵ is Selected from One of the Following Groups (12a)-(12k):

-   -   (12a) R⁵ is hydrogen, halogen, C₁₋₆alkyl, —OR⁵⁰, —NR⁵⁰R⁵⁰,        —N(R⁵⁰)C(O)R⁵⁰, or —N(R⁵⁰)S(O)₂R⁵⁰, wherein each R⁵⁰ is        independently hydrogen or C₁₋₆alkyl.    -   (12b) R⁵ is hydrogen, halogen, C₁₋₄alkyl, —OR⁵⁰, —NR⁵⁰R⁵⁰,        —N(R⁵⁰)C(O)R⁵⁰, or —N(R⁵⁰)S(O)₂R⁵⁰, wherein each R⁵⁰ is        independently hydrogen or C₁₋₄alkyl.    -   (12c) R⁵ is hydrogen, fluoro, chloro, methyl, methoxy, ethoxy,        amino, acetylamino, or methylsulfonylamino    -   (12d) R⁵ is fluoro or chloro    -   (12e) R⁵ is fluoro    -   (12f) R⁵ is chloro    -   (12g) R⁵ is methyl    -   (12h) R⁵ is methoxy or ethoxy    -   (12i) R⁵ is amino, acetylamino, or methylsulfonylamino    -   (12j) R⁵ is hydrogen.    -   (12k) any one of (12a)-(12i), where R⁵ is not hydrogen.

R⁶ is Selected from One of the Following Groups (13a)-(13k):

-   -   (13a) R⁶ is hydrogen, halogen, C₁₋₆alkyl, —OR⁶⁰, —NR⁶⁰R⁶⁰,        —N(R⁶⁰)C(O)R⁶⁰, or —N(R⁶⁰)S(O)₂R⁶⁰, wherein each R⁶⁰ is        independently hydrogen or C₁₋₆alkyl.    -   (13b) R⁶ is hydrogen, halogen, C₁₋₄alkyl, —OR⁶⁰, —NR⁶⁰R⁶⁰,        —N(R⁶⁰)C(O)R⁶⁰, or —N(R⁶⁰)S(O)₂R⁶⁰, wherein each R⁶⁰ is        independently hydrogen or C₁₋₄alkyl.    -   (13c) R⁶ is hydrogen, fluoro, chloro, methyl, methoxy, ethoxy,        amino, acetylamino, or methylsulfonylamino    -   (13d) R⁶ is fluoro or chloro    -   (13e) R⁶ is fluoro    -   (13f) R⁶ is chloro    -   (13g) R⁶ is methyl    -   (13h) R⁶ is methoxy or ethoxy    -   (13i) R⁶ is amino, acetylamino, or methylsulfonylamino    -   (13j) R⁶ is hydrogen.    -   (13k) any one of (13a)-(13j), where R⁶ is not hydrogen.

R⁵ and R⁶ are Selected from One of the Following Groups (14a)-(140):

-   -   (14a) R⁵ and R⁶ are each independently hydrogen, halogen,        C₁₋₆alkyl, —OR⁷, —NR⁷R⁷, —N(R⁷)C(O)R⁷, or —N(R⁷)S(O)₂R⁷, wherein        each R⁷ is independently hydrogen or C₁₋₆alkyl.    -   (14b) one of R⁵ and R⁶ is hydrogen, and the other is halogen,        C₁₋₆alkyl, —OR⁷, —NR⁷R⁷, —N(R⁷)C(O)R⁷, or —N(R⁷)S(O)₂R⁷, wherein        each R⁷ is independently hydrogen or C₁₋₆alkyl.    -   (14c) R⁵ and R⁶ are each independently hydrogen, halogen,        C₁₋₄alkyl, —OR⁷, —NR⁷R⁷, —N(R⁷)C(O)R⁷, or —N(R⁷)S(O)₂R⁷, wherein        each R⁷ is independently hydrogen or C₁₋₄alkyl.    -   (14d) one of R⁵ and R⁶ is hydrogen, and the other is halogen,        C₁₋₄alkyl, —OR⁷, —NR⁷R⁷, —N(R⁷)C(O)R⁷, or —N(R⁷)S(O)₂R⁷, wherein        each R⁷ is independently hydrogen or C₁₋₄alkyl.    -   (14e) R⁵ and R⁶ are each independently hydrogen, fluoro, chloro,        methyl, methoxy, ethoxy, amino, acetylamino, or        methylsulfonylamino    -   (14f) one of R⁵ and R⁶ is hydrogen, and the other is fluoro,        chloro, methyl, methoxy, ethoxy, amino, acetylamino, or        methylsulfonylamino    -   (14g) any one of (14a)-(14f), where one of R⁵ and R⁶ is not        hydrogen.    -   (14h) R⁵ and R⁶ are each hydrogen    -   (14i) one of R⁵ and R⁶ is hydrogen, and the other is fluoro, or        chloro    -   (14j) one of R⁵ and R⁶ is hydrogen, and the other is methyl    -   (14k) one of R⁵ and R⁶ is hydrogen, and the other is methoxy or        ethoxy    -   (14l) one of R⁵ and R⁶ is hydrogen, and the other is amino,        acetylamino, or methylsulfonylamino    -   (14m) one of R⁵ and R⁶ is hydrogen, and the other is amino    -   (14n) one of R⁵ and R⁶ is hydrogen, and the other is acetylamino    -   (14o) one of R⁵ and R⁶ is hydrogen, and the other is        methylsulfonylamino

R^(Z1) is Selected from One of the Following Groups (15a)-(151):

-   -   (15a) R^(Z1) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, C₃₋₈        cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl),        heteroaryl(C₁₋₆alkyl), —R^(Z3), —C₁₋₆alkyl-R^(Z3), or        —C₁₋₆alkyl-R^(Z4), wherein R^(Z3) is —C(O)R, —C(O)OR, —C(O)NR₂,        or —S(O)₂NR₂; and R^(Z4) is —OR, —SR, —NR₂, —OC(O)R, —N(R)C(O)R,        —OC(O)OR, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)NR₂, —N(R)S(O)₂R, or        —OP(O)(OR)₂.    -   (15b) R^(Z1) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, C₃₋₈        cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl),        heteroaryl(C₁₋₆alkyl), —R^(Z3), —C₁₋₆alkyl-R^(Z3), or        —C₁₋₆alkyl-R^(Z4), wherein R^(Z3) is —C(O)R^(Z6), —C(O)OR^(Z6),        —C(O)NR^(Z6) ₂, or —S(O)₂NR^(Z5) ₂; and R^(Z4) is —OR^(Z5),        —SR^(Z5), —NR^(Z5) ₂, —OC(O)R^(Z5), —N(R^(Z5))C(O)R^(Z5),        —OC(O)OR^(Z5), —OC(O)NR^(Z5) ₂, —N(R^(Z5))C(O)OR^(Z5),        —N(R^(Z5))C(O)NR^(Z5) ₂, —N(R^(Z5))S(O)₂R^(Z5), or        —OP(O)(OR^(Z5))₂, and wherein each R^(Z5) is independently        hydrogen or C₁₋₆alkyl; and each R^(Z6) is independently hydrogen        or C₁₋₆alkyl, C₃₋₈cycloalkyl(C₁₋₆alkyl),        heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), or        heteroaryl(C₁₋₆alkyl), each optionally substituted by one or two        groups that are each independently —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰,        —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰, —N(R⁰)C(O)R⁰,        —OC(O)OR⁰, —OC(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰, —N(R⁰)C(O)N(R⁰)₂, or        —N(R⁰)S(O)₂R⁰, wherein each R⁰ is independently hydrogen or        C₁₋₆alkyl.    -   (15c) R^(Z1) is hydrogen, C₁₋₆alkyl, heterocyclyl,        heterocyclyl(C₁₋₆alkyl), —C₁₋₆alkyl-R^(Z4), or —C(O)OR^(Z6),        wherein R^(Z4) is —OR^(Z5), —SR^(Z5), —NR^(Z5) ₂, —OC(O)R^(Z5),        —N(R^(Z5))C(O)R^(Z5), —OC(O)OR^(Z5), —OC(O)NR^(Z5) ₂,        —N(R^(Z5))C(O)OR^(Z5), —N(R^(Z5))C(O)NR^(Z5) ₂,        —N(R^(Z5))S(O)₂R^(Z5), or —OP(O)(OR^(Z5))₂, wherein the        heterocyclyl and heterocyclyl(C₁₋₆alkyl) are each optionally        substituted by one or two groups that are each independently        halogen or C₁₋₆alkyl; and wherein each R^(Z5) is independently        hydrogen or C₁₋₆alkyl; and each R^(Z6) is independently hydrogen        or C₁₋₆alkyl, C₃₋₈cycloalkyl(C₁₋₆alkyl),        heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), or        heteroaryl(C₁₋₆alkyl), each optionally substituted by —OR⁰,        —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, or —C(O)N(R⁰)₂, wherein each        R⁰ is independently hydrogen or C₁₋₆alkyl.    -   (15d) R^(Z1) is hydrogen, C₁₋₆alkyl, heterocyclyl,        heterocyclyl(C₁₋₆alkyl), —C₁₋₆alkyl-OR^(Z5), or        —C₁₋₆alkyl-OP(O)(OR^(Z5))₂, or —C(O)OR^(Z6), wherein the        heterocyclyl and heterocyclyl(C₁₋₆alkyl) are each optionally        substituted by one or two C₁₋₆alkyl groups; and wherein each        R^(Z5) is independently hydrogen or C₁₋₆alkyl; each R^(Z6) is        independently hydrogen or C₁₋₆alkyl or heteroaryl(C₁₋₆alkyl),        each optionally substituted by —OR⁰, or —N(R⁰)₂, wherein each R⁰        is independently hydrogen or C₁₋₆alkyl.    -   (15e) R^(Z1) is hydrogen, methyl, ethyl, isopropyl,        2-(morpholin-4-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl,        3-hydroxypropyl, 3-ethoxypropyl, 4-tetrahydropyranyl,        N-methylpiperidin-4-yl, —CH₂—OP(O)(OH)₂, or        3-(indol-3-yl)-2-aminopropyloxycarbonyl.    -   (15f) R^(Z1) is hydrogen, methyl, or        3-(indol-3-yl)-2-aminopropyloxycarbonyl.    -   (15g) R^(Z1) is hydrogen or methyl.    -   (15h) R^(Z1) is hydrogen.    -   (15i) R^(Z1) is methyl.    -   (15j) R^(Z1) is 3-(indol-3-yl)-2-aminopropyloxycarbonyl.

R^(Z2) is Selected from One of the Following Groups (16a)-(16d):

-   -   (16a) R^(Z2) is hydrogen or halogen    -   (16b) R^(Z2) is hydrogen or C₁₋₆alkyl;    -   (16c) R^(Z2) is hydrogen or methyl;    -   (16d) R^(Z2) is hydrogen

Particular embodiments of this aspect of the disclosure includecompounds of any one of the Formula (II), each as defined in each of thefollowing rows, wherein each entry is a group number as defined above,and a dash “—” indicates that the variable is as defined for formula(II) or defined according to any one of the applicable variabledefinitions (9a)-(16d) [e.g., when R^(Z1) is a dash, it can be either asdefined for Formula (II) or any one of definitions (15a)-(15j)]:

R¹ & R² R⁵ & R⁶ R^(Z1) R^(Z2) (11d) (14e) (15e) (16a) (11d) (14e) (15e)(16b) (11d) (14e) (15g) (16a) (11d) (14e) (15g) (16b) (11d) (14f) (15e)(16a) (11d) (14f) (15e) (16b) (11d) (14f) (15g) (16a) (11d) (14f) (15g)(16b) (11d) (14h) (15e) (16a) (11d) (14h) (15e) (16b) (11d) (14h) (15g)(16a) (11d) (14h) (15g) (16b) (11d) (14i) (15e) (16a) (11d) (14i) (15e)(16b) (11d) (14i) (15g) (16a) (11d) (14i) (15g) (16b) (11e) (14e) (15e)(16a) (11e) (14e) (15e) (16b) (11e) (14e) (15g) (16a) (11e) (14e) (15g)(16b) (11e) (14f) (15e) (16a) (11e) (14f) (15e) (16b) (11e) (14f) (15g)(16a) (11e) (14f) (15g) (16b) (11e) (14h) (15e) (16a) (11e) (14h) (15e)(16b) (11e) (14h) (15g) (16a) (11e) (14h) (15g) (16b) (11e) (14i) (15e)(16a) (11e) (14i) (15e) (16b) (11e) (14i) (15g) (16a) (11e) (14i) (15g)(16b) (11f) (14e) (15e) (16a) (11f) (14e) (15e) (16b) (11f) (14e) (15g)(16a) (11f) (14e) (15g) (16b) (11f) (14f) (15e) (16a) (11f) (14f) (15e)(16b) (11f) (14f) (15g) (16a) (11f) (14f) (15g) (16b) (11f) (14h) (15e)(16a) (11f) (14h) (15e) (16b) (11f) (14h) (15g) (16a) (11f) (14h) (15g)(16b) (11f) (14i) (15e) (16a) (11f) (14i) (15e) (16b) (11f) (14i) (15g)(16a) (11f) (14i) (15g) (16b)

In certain embodiments of the compounds as described throughout thisdisclosure, Z is optionally substituted by one or two groups that areeach independently halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —R^(Z), or—C₁₋₆alkyl-R^(Z), wherein each and R^(Z) is cyano, —CF₃, —OR, —SR,—NR^(a)R^(a), —C(O)R, —C(O)OR, —C(O)NR^(a)R^(a), —S(O)₂NR^(a)R^(a),—S(O)₂R⁰, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR^(a)R^(a), —N(R)C(O)OR,—N(R)C(O)NR^(a)R^(a), —N(R)S(O)₂R, or —OP(O)(OR)₂. In certain suchembodiments, each R is independently hydrogen, C₁₋₆alkyl, orC₁₋₆haloalkyl, each optionally substituted by 1-3 groups that are eachindependently R^(b), —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰,—C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰, —N(R⁰)C(O)R⁰, —OC(O)OR⁰,—O(CH₂)_(m)C(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰, —N(R⁰)C(O)N(R⁰)₂, or—N(R⁰)S(O)₂R⁰, in which each R^(b) is independently halogen, cyano, oxo,C₁₋₆alkyl, C₁₋₆haloalkyl or —OR¹³, in which R¹³ is hydrogen, C₁₋₆alkylor C₁₋₆haloalkyl, each optionally substituted by 1-3 groups that areeach independently halogen, cyano, oxo, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR⁰,—SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰,—N(R⁰)C(O)R⁰, —OC(O)OR⁰, —O(CH₂)_(m)C(O)N(R)₂, —N(R⁰)C(O)OR⁰,—N(R⁰)C(O)N(R⁰)₂, or —N(R⁰)S(O)₂R⁰, in which each R⁰ is independentlyhydrogen, C₁₋₆haloalkyl or C₁₋₆alkyl optionally substituted with 1-3R^(b0), in which each R^(b0) is independently independently halogen,cyano or oxo.

In certain embodiments of the compounds as described throughout thisdisclosure, each R^(a) is independently hydrogen, C₁₋₆alkyl orC₁₋₆haloalkyl, each optionally substituted by 1-3 groups that are eachindependently R^(b), —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰,—C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰, —N(R⁰)C(O)R⁰, —OC(O)OR⁰,—O(CH₂)_(m)C(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰, —N(R⁰)C(O)N(R⁰)₂, or—N(R⁰)S(O)₂R⁰, or two R^(a) together with the nitrogen atom to whichthey are attached form a 3-8 membered heterocyclyl group, optionallyincluding 1-4 additional heteroatoms selected from O, N and S andoptionally substituted with 1-4 R groups.

In certain embodiments of the compounds as described throughout thisdisclosure, each R^(b) is independently halogen, cyano, oxo, C₁₋₆alkyl,C₁₋₆haloalkyl or —OR¹¹, in which R¹² is hydrogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), orheteroaryl(C₁₋₆alkyl), each optionally substituted by 1-3 groups thatare each independently halogen, cyano, oxo, C₁₋₆alkyl, C₁₋₆haloalkyl,—OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂,—OC(O)R⁰, —N(R⁰)C(O)R⁰, —OC(O)OR⁰, —O(CH₂)_(m)C(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰,—N(R⁰)C(O)N(R⁰)₂, or —N(R⁰)S(O)₂R⁰, in which each R⁰ is independentlyhydrogen, C₁₋₆haloalkyl, C₁₋₆alkyl optionally substituted with 1-3R^(b0), C₃₋₈cycloalkyl optionally substituted with one or two R^(b0) or,alternatively two R⁰ together with a nitrogen atom to which they arebound (for example when R is —C(O)N(R⁰)₂) form a 3-8 memberedheterocyclyl group, optionally including 1-4 additional heteroatomsselected from O, N and S and optionally substituted with 0-3 R^(b0), inwhich each R^(b0) is independently independently halogen, cyano or oxo.

In certain embodiments of the compounds as described throughout thisdisclosure, each R^(b) is independently halogen, cyano, oxo, C₁₋₆alkyl,C₁₋₆haloalkyl or —OR¹³, in which R¹³ is hydrogen, C₁₋₆alkyl orC₁₋₆haloalkyl, each optionally substituted by 1-3 groups that are eachindependently halogen, cyano, oxo, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR⁰, —SR⁰,—N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰,—N(R⁰)C(O)R⁰, —OC(O)OR⁰, —O(CH₂)_(m)C(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰,—N(R⁰)C(O)N(R⁰)₂, or —N(R⁰)S(O)₂R⁰, in which each R⁰ is independentlyhydrogen, C₁₋₆haloalkyl or C₁₋₆alkyl optionally substituted with 1-3R^(b0), in which each R^(b0) is independently independently halogen,cyano or oxo.

In certain embodiments of the compounds as described throughout thisdisclosure, each R is independently hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), orheteroaryl(C₁₋₆alkyl), each optionally substituted by 1-3 groups thatare each independently R^(b), —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰,—C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰, —N(R⁰)C(O)R⁰, —OC(O)OR⁰,—O(CH₂)_(m)C(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰, —N(R⁰)C(O)N(R⁰)₂, or—N(R⁰)S(O)₂R⁰. In certain such embodiments, each R⁰ is hydrogen,C₁₋₆haloalkyl or C₁₋₆alkyl.

In certain embodiments of the compounds as described throughout thisdisclosure, each R is independently hydrogen, C₁₋₆alkyl, orC₁₋₆haloalkyl, each optionally substituted by 1-3 groups that are eachindependently R^(b0), —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰,—C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰, —N(R⁰)C(O)R⁰, —OC(O)OR⁰,—O(CH₂)_(m)C(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰, —N(R⁰)C(O)N(R⁰)₂, or—N(R⁰)S(O)₂R⁰, in which each R^(b) is independently halogen, cyano, oxo,C₁₋₆alkyl, C₁₋₆haloalkyl or —OR¹³, in which R¹³ is hydrogen, C₁₋₆alkylor C₁₋₆haloalkyl, each optionally substituted by 1-3 groups that areeach independently halogen, cyano, oxo, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR⁰,—SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰,—N(R⁰)C(O)R⁰, —OC(O)OR⁰, —O(CH₂)_(m)C(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰,—N(R⁰)C(O)N(R⁰)₂, or —N(R⁰)S(O)₂R⁰, in which each R⁰ is independentlyhydrogen, C₁₋₆haloalkyl or C₁₋₆alkyl optionally substituted with 1-3R^(b0), in which each R^(b0) is independently independently halogen,cyano or oxo.

In certain embodiments of the compounds as described throughout thisdisclosure, R⁰ is independently hydrogen, C₁₋₆haloalkyl, or C₁₋₆alkyloptionally substituted with 1-3 R^(b0), in which each R^(b0) isindependently independently halogen, cyano or oxo.

In certain embodiments of the compounds as described throughout thisdisclosure, each C₁₋₆(halo)alkyl is a C₁₋₃(halo)alkyl. In otherembodiments of the compounds as described throughout this disclosure,each C₁₋₆(halo)alkyl is a C₁₋₂(halo)alkyl.

In certain embodiments of the compounds as described throughout thisdisclosure, when R¹ and R² are attached to adjacent carbon atoms theyare optionally taken together with the atoms to which they are attachedto form a 5- or 6-membered ring optionally substituted with one or twogroups that are each independently halogen, oxo, oxime, imino,C₁₋₆alkyl, C₁₋₆haloalkyl, or —R¹⁰. The ring can be for example, an arylring (e.g., a benzo) or a 5- or 6-membered heteroaryl ring (e.g. apyrido or a thieno). When the ring is a heteroaryl ring, it can include1 or 2 heteroatoms selected from N, O and S. In other embodiments, thering is a cycloalkylene (e.g., 5 or 6 membered), or a heterocyclyl ring(e.g., 5 or 6 membered) including 1 or 2 heteroatoms selected from N, Oand S.

In certain embodiments, the compound of formula (I) is one of thecompounds of Table 1, optionally provided as a salt (e.g., the saltindicated in the Table):

Cpd # Structure Salt 1

TFA(2) 2

TFA(2) 3

Formic Acid(2) 4

Formic Acid(2) 5

Formic Acid(2) 6

TFA(2) 7

TFA(2) 8

Formic Acid(2) 9

TFA(2) 10

TFA(2) 11

TFA(2) 12

TFA(2) 13

TFA(2) 14

TFA(2) 15

TFA(3) 16

TFA(3) 17

Formic Acid(3) 18

TFA(3) 19

TFA(3) 20

TFA(3) 21

TFA(3) 22

TFA(3) 23

TFA(3) 24

TFA(2) 25

TFA(2) 26

TFA(2) 27

TFA(3) 28

TFA(3) 29

TFA(3) 30

TFA(2) 31

TFA(2) 32

TFA(2) 33

Parent 34

Parent 35

Parent 36

Parent 37

Parent 38

Parent 39

Parent 40

Parent 41

Parent 42

Parent 43

Parent 44

Parent 45

Parent 46

Parent 47

Parent 48

Parent 49

Parent 50

Parent 51

Parent 52

Parent 53

Parent 54

Parent 55

Parent 56

Parent 57

Parent 58

Parent 59

Parent 60

Parent 61

Parent 62

Parent 63

Parent 64

Parent 65

Parent 66

Parent 67

Parent 68

Parent 69

Parent 70

Parent 71

Parent 72

Parent 73

Parent 74

Parent 75

Parent 76

Parent 77

Parent 78

Parent 79

Parent 80

Parent 81

Parent 82

Parent 83

Parent 84

Parent 85

Parent 86

Parent 87

Parent 88

Parent 89

Parent 90

Parent 91

Parent 92

Parent 93

Parent 94

Parent 95

Parent 96

Parent 97

Parent 98

Parent 99

Parent 100

Parent 101

Parent 102

Parent 103

Parent 104

Parent 105

Parent 106

Parent 107

Parent 108

Parent 109

Parent 110

Parent 111

Parent 112

Parent 113

Parent 114

Parent 115

Parent 116

Parent 117

Parent 118

Parent 119

Parent 120

Parent 121

Parent 122

Parent 123

Parent 124

Parent 125

Parent 126

Parent 127

Parent 128

Parent 129

Parent 130

Parent 131

Parent 132

Parent 133

Parent 134

Parent 135

Parent 136

Parent 137

Parent 138

Parent 139

Parent 140

Parent 141

Parent 142

Parent 143

Parent 144

Parent 145

Parent 146

Parent 147

Parent 148

Parent 149

Parent 150

Parent 151

Parent 152

Parent 153

Parent 154

Parent 155

Parent 156

Parent 157

Parent 158

Parent 159

Parent 160

Parent 161

Parent 162

Parent 163

Parent 164

Parent 165

Parent 166

Parent 167

Parent 168

Parent 169

Parent 170

Parent 171

Parent 172

Parent 173

Parent 174

Parent 175

Parent 176

Parent 177

Parent 178

Parent 179

TFA 180

Parent 181

Parent 182

Parent 183

Parent 184

Parent 185

Parent 186

Parent 187

Parent 188

Parent 189

Parent 190

Parent 191

Parent 192

Parent 193

Parent 194

Parent 195

Parent 196

Parent 197

Parent 198

Parent 199

Parent 200

Parent 201

Parent 202

Parent 203

Parent 204

Parent 205

Parent 206

Parent 207

Parent 208

Parent 209

Parent 210

Parent 211

TFA(3) 212

TFA(3) 213

TFA(2) 214

TFA(2) 215

TFA(2) 216

TFA(2) 217

TFA(2) 218

TFA(3) 219

TFA(3) 220

TFA(3) 221

TFA(3) 222

Parent 223

TFA(3) 224

TFA(3) 225

TFA(2) 226

TFA(3) 227

Parent 228

TFA(3) 229

TFA 230

TFA(3) 231

TFA 232

TFA(2) 233

TFA(3) 234

TFA 235

TFA(2) 236

TFA 237

TFA(2) 238

TFA(2) 239

TFA(2) 240

TFA(3) 241

TFA(2) 242

TFA(2) 243

TFA(2) 244

TFA(3) 245

TFA(3) 246

TFA(3) 247

TFA(3) 248

Parent 249

Parent 250

Parent 251

Parent 252

Parent 253

Parent 254

Parent 255

Parent 256

Parent 257

Parent 258

Parent 259

Parent 260

Parent 261

Parent 262

Parent 263

Parent 264

Parent 265

Parent 266

Parent 267

Parent 268

Parent 269

Parent 270

Parent 271

Parent 272

Parent 273

Parent 274

Parent 275

Parent 276

Parent 277

Parent 278

Parent 279

Parent 280

Parent 281

Parent 282

Parent 283

Parent 284

Parent 285

Parent 286

Parent 287

Parent 288

Parent 289

Parent 290

Parent 291

Parent 292

Parent 296

Parent 294

Parent 295

Parent 296

Parent 297

Parent 298

Parent 299

Parent 300

Parent 301

Parent 302

Parent 303

Parent 304

Parent 305

Parent 306

TFA(3) 307

Parent 308

Formic Acid(2) 309

Formic Acid(2) 310

TFA(2) 311

Formic Acid(3) 312

Formic Acid(2) 313

Formic Acid(1) 314

Formic Acid(2) 315

Formic Acid(2) 316

Formic Acid(2) 317

Formic Acid(2) 318

Formic Acid(2) 319

Formic Acid(3) 320

Formic Acid(3) 321

TFA(3) 322

Formic Acid(3) 323

Formic Acid(3) 324

Formic Acid(3) 325

Formic Acid(3) 326

Formic Acid(3) 327

Formic Acid(3) 328

TFA(3) 329

Formic Acid(3) 330

Formic Acid(3) 331

Formic Acid(3) 332

Formic Acid(3) 333

Formic Acid(2) 334

Formic Acid(2) 335

Formic Acid(3) 336

Formic Acid(3) 337

Formic Acid(3) 338

Formic Acid(3) 339

Formic Acid(3) 340

Formic Acid(2) 341

Formic Acid(2) 342

Formic Acid(2) 343

TFA(2) 344

TFA(2) 345

TFA(3) 346

Formic Acid(2) 347

Formic Acid(3) 348

TFA(2) 349

TFA(2) 350

TFA(2) 351

Formic Acid(3) 352

Formic Acid(3) 353

Formic Acid(3) 354

Formic Acid(3) 355

Formic Acid(3) 356

Formic Acid(3) 357

Formic Acid(3) 358

Formic Acid(3) 359

Formic Acid(3) 360

TFA(3) 361

Formic Acid(2) 362

Formic Acid(2) 363

TFA(3) 364

TFA(3) 365

TFA(3) 366

Formic Acid(3) 367

Formic Acid(3) 368

Formic Acid(3) 369

Formic Acid(3) 370

Formic Acid(3) 371

Formic Acid(3) 372

Formic Acid(3) 373

Formic Acid(3) 374

Formic Acid(3) 375

Formic Acid(2) 376

Formic Acid(2) 377

Formic Acid(2) 378

Formic Acid(2) 379

Formic Acid(2) 380

Formic Acid(2) 381

Formic Acid(2) 382

Formic Acid(2) 383

Formic Acid(3) 384

Formic Acid(3) 385

TFA(3) 386

TFA(3) 387

TFA(3) 388

Parent 389

Parent 390

TFA(2) 391

TFA(2) 392

Formic Acid(3) 393

Formic Acid(3) 394

Formic Acid(3) 395

Formic Acid(2) 396

Formic Acid(2) 397

Formic Acid(3) 398

Formic Acid(3) 399

Formic Acid(3) 400

Formic Acid(3) 401

Formic Acid(3) 402

Formic Acid(3) 403

Formic Acid(3) 404

Formic Acid(3) 405

Formic Acid(3) 406

Formic Acid(3) 407

Formic Acid(3) 408

Formic Acid(3) 409

Formic Acid(2) 410

Formic Acid(2) 411

Formic Acid(3) 412

Formic Acid(3) 413

Formic Acid(3) 414

Formic Acid(3) 415

Formic Acid(3) 416

Formic Acid(3) 417

Formic Acid(3) 418

Formic Acid(2) 419

Formic Acid(2) 420

Formic Acid(2) 421

Formic Acid(3) 422

Formic Acid(3) 423

TFA(3) 424

TFA(3) 425

Formic Acid(3) 426

Formic Acid(2) 427

Formic Acid(2) 428

Formic Acid(2) 429

Formic Acid(3) 430

Formic Acid(3) 431

Formic Acid(2) 432

Formic Acid(3) 433

Formic Acid(3) 434

Formic Acid(3) 435

Formic Acid(3) 436

Formic Acid(3) 437

Formic Acid(3) 438

Formic Acid(3) 439

Formic Acid(3) 440

Formic Acid(2) 441

Formic Acid(2) 442

Formic Acid(3) 443

Formic Acid(3) 444

Formic Acid(3) 445

Formic Acid(3) 446

Formic Acid(3) 447

Formic Acid(3) 448

Parent 449

TFA(3) 450

TFA(3) 451

TFA(3) 452

TFA(3) 453

TFA(3) 454

TFA(3) 455

TFA(3) 456

TFA(3) 457

TFA(3) 458

Formic Acid(3) 459

Formic Acid(3) 460

Formic Acid(3) 461

Formic Acid(3) 462

Formic Acid(3) 463

Formic Acid(3) 464

Formic Acid(3) 465

Formic Acid(3) 466

Formic Acid(3) 467

Formic Acid(3) 468

Formic Acid(3) 469

Formic Acid(3) 470

Formic Acid(3) 471

Formic Acid(3) 472

Formic Acid(3) 473

Formic Acid(3) 474

Formic Acid(3) 475

Formic Acid(3) 476

Formic Acid(3) 477

Formic Acid(3) 478

Formic Acid(3) 479

Formic Acid(3) 480

Formic Acid(3) 481

Formic Acid(3) 482

Formic Acid(3) 483

Formic Acid(3) 484

Formic Acid(3) 485

Formic Acid(3) 486

Formic Acid(3) 487

Formic Acid(3) 488

Formic Acid(3) 489

Formic Acid(3) 490

Formic Acid(3) 491

Parent 492

Formic Acid(3) 493

Formic Acid(3) 494

Formic Acid(3) 495

Formic Acid(3) 496

Parent 497

Formic Acid(3) 498

Formic Acid(3) 499

Formic Acid(3) 500

Formic Acid(3) 501

Formic Acid(3) 502

Formic Acid(3) 503

Formic Acid(3) 504

Formic Acid(3) 505

Formic Acid(3) 506

Formic Acid(2) 507

TFA(2) 508

Parent 509

TFA(3) 510

Parent 511

Parent 512

Parent 513

Parent 514

Parent 515

Parent 516

Parent 517

Parent 518

Parent 519

Parent 520

Parent 521

Parent 522

Parent 523

Parent 524

Parent 525

Parent 526

Parent 527

Parent 528

Parent 529

Parent 530

Parent 531

Parent 532

Parent 533

Parent 534

Parent 535

Parent 536

Parent 537

Parent 538

Parent 539

Parent 540

Parent 541

Parent 542

Parent 543

Parent 544

Parent 545

Parent 546

Parent 547

Parent 548

Parent 549

Parent 550

Parent 551

Parent 552

Parent 553

Parent 554

Parent 555

Parent 556

Parent 557

Parent 558

Parent 559

Parent 560

Parent 561

Parent 562

Parent 563

Parent 564

Parent 565

Parent 566

Parent 567

Parent 568

Parent 569

Parent 570

Parent 571

Parent 572

Parent 573

Parent 574

Parent 575

Parent 576

Parent 577

Parent 578

Parent 579

Parent 580

Parent 581

Parent 582

Parent 583

Parent 584

Parent 585

Parent 586

Parent 587

Parent 588

Parent 589

Parent 590

Parent 591

Parent 592

Parent 593

Parent 594

Parent 595

Parent 596

Parent 597

Parent 598

Parent 599

Parent 600

Parent 601

Parent 602

Parent 603

Parent 604

Parent 605

Parent 606

Parent 607

Parent 608

Parent 609

Parent 610

Parent 611

Parent 612

Parent 613

Parent 614

Parent 615

Formic Acid(1) 616

Parent 617

Parent 618

Parent 619

Parent 620

Formic Acid(1) 621

Parent 622

Parent 623

Parent 624

Parent 625

Parent 626

Parent 627

Parent 628

Parent 629

TFA 630

Parent 631

Parent 632

Parent 633

Parent 634

Parent 635

Parent 636

Parent 637

Parent 638

Parent 639

Parent 640

Parent 641

Parent 642

Parent 643

Parent 644

Parent 645

Formic Acid(1) 646

Formic Acid(1) 647

Formic Acid(1) 648

Parent 649

HCl 650

HCl 651

Parent 652

Parent 653

Parent 654

Parent 655

Parent 656

Parent 657

Parent 658

Parent 659

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Parent TFA = trifluoroacetate salt (2) = bis(acid) salt (3) = tris(acid)salt Parent = free base compound

General Synthetic Methodologies

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith and March, March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Fifth Edition,Wiley-Interscience, 2001; or Vogel, A Textbook of Practical OrganicChemistry, Including Qualitative Organic Analysis, Fourth Edition, NewYork: Longman, 1978).

Compounds as described herein can be purified by any of the means knownin the art, including chromatographic means, such as HPLC, preparativethin layer chromatography, flash column chromatography and ion exchangechromatography. Any suitable stationary phase can be used, includingnormal and reversed phases as well as ionic resins. Most typically thedisclosed compounds are purified via silica gel and/or aluminachromatography. See, e.g., Introduction to Modern Liquid Chromatography,2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons,1979; and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, NewYork, 1969.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas J. F. W. McOmie, “Protective Groups in Organic Chemistry”, PlenumPress, London and New York 1973, in T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer),Academic Press, London and New York 1981, in “Methoden der organischenChemie”, Houben-Weyl, 4.sup.th edition, Vol. 15/1, Georg Thieme Verlag,Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide,Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982,and/or in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide andDerivate”, Georg Thieme Verlag, Stuttgart 1974. The protecting groupsmay be removed at a convenient subsequent stage using methods known fromthe art.

The compounds disclosed herein can be made using procedures familiar tothe person of ordinary skill in the art and as described herein. Forexample, compounds of structural formula (I) can be prepared accordingto Schemes 1-49, or analogous synthetic schemes.

As is known to those of skill in the art of organic synthesis, estersand amides can be formed from the corresponding acids, alcohols andamines by conventional techniques. By way of example, organic acids canbe converted to the corresponding acid chloride by reaction with oxalylchloride. Acid chlorides can then be reacted with alcohols or amines toform the desired ester or amide, as shown in Schemes 1-4. Alternatively,activating reagents like HATU, TBTU or HBTU can be used in to condensean amine can be condensed with an organic acid to form the correspondingamide, as shown in Scheme 5.

Boronate coupling reactions can be used to make certain compoundsdescribed herein, e.g., in the formation of (hetero)aryl-(hetero)arylbonds. For example, compounds such as compounds 601-606 can be preparedas shown in Scheme 6.

Compounds such as compounds 598 and 599 can be made using reduction andGrignard addition, respectively, as shown in Scheme 7.

Carboxylic acids can be formed by hydrolysis of the correspondingnitrile, as shown for Compound 579 in Scheme 8. Carboxylic esters (e.g.,compounds 677 and 685) can be prepared and hydrolyzed to thecorresponding acid (e.g., compound 579) as shown in Schemes 9 and 10.The person of ordinary skill in the art will appreciate that a widevariety of other compounds described herein can be made using thegeneral synthetic paths of Schemes 9 and 10, suitably adapted to providethe desired functional groups in the final molecule.

Pyrimidinyl compounds can be made via the reaction sequence shown inScheme 11.

Various additional compounds of the disclosure can be made using thereactions shown in Schemes 12-27.

The conditions for boronate cross-coupling to form Compound 448 wereineffective when the corresponding bromopyrido[3,2-d]pyrimidine wasused. Scheme 28 provides an alternative route to thepyrido[3,2-d]pyrimidine products.

One of skill in the art can adapt the reaction sequences of Schemes 1-28to fit the desired target molecule. Of course, in certain situations oneof skill in the art will use different reagents to affect one or more ofthe individual steps or to use protected versions of certain of thesubstituents. Additionally, one skilled in the art would recognize thatthe compounds described herein can be synthesized using different routesaltogether.

2-Chloro-3-(hetero)arylpyridine compounds

In another aspect, the present disclosure includes novel intermediatesuseful to prepare the present kinase inhibitors as well as otherpharmaceutically effective compounds as is readily apparent to those ofskill in the art of medicinal chemistry. For example, the2-chloro-3-(hetero)arylpyridine compounds described herein are suitablefor cross coupling, by for example, palladium mediated chemistry, suchas a Suzuki reaction, to form the kinase inhibitors disclosed herein aswell as other novel biologically active compounds.2-Chloro-3-(hetero)arylpyridine compounds according to this aspect ofthe disclosure are described throughout the present specification.

Methods of Treating Disease

The compounds of the present disclosure are useful to prevent, diagnose,and treat various medical disorders in humans or animals. The compoundsare used to inhibit or reduce one or more activities associated with theGDF protein, relative to a GDF protein not bound by the same compounds.Optionally, the compounds inhibit or reduce one or more of theactivities of mature GDF-8 (regardless of whether in monomeric form,active dimeric form, or complexed in a GDF-8 latent complex) relative toa mature GDF-8 protein that is not bound by the same compounds. In anembodiment, the activity of the mature GDF-8 protein, when bound by oneor more of the presently disclosed compounds, is inhibited at least 50%,optionally at least 60, 62, 64, 66, 68, 70, 72, 72, 76, 78, 80, 82, 84,86, or 88%, optionally at least 90, 91, 92, 93, or 94%, and optionallyat least 95% to 100% relative to a mature GDF-8 protein that is notbound by one or more of the presently disclosed compounds.

The medical disorder being diagnosed, treated, or prevented by thepresently disclosed compounds is optionally a muscle and neuromusculardisorder; an adipose tissue disorder such as obesity; type 2 diabetes,impaired glucose tolerance, metabolic syndromes (e.g., syndrome X),insulin resistance induced by trauma such as burns; or bone degenerativedisease such as osteoporosis. The medical condition is optionally amuscle or neuromuscular disorder, such as muscular dystrophy, muscleatrophy, congestive obstructive pulmonary disease, muscle wastingsyndrome, sarcopenia, or cachexia and disorders associated with a lossof bone, which include osteoporosis, especially in the elderly and/orpostmenopausal women, glucocorticoid-induced osteoporosis, osteopenia,and osteoporosis-related fractures. Other target metabolic bone diseasesand disorders amendable to treatment with GDF-8 inhibitors of thedisclosure include low bone mass due to chronic glucocorticoid therapy,premature gonadal failure, androgen suppression, vitamin D deficiency,secondary hyperparathyroidism, nutritional deficiencies, and anorexianervosa. The antibodies are optionally used to prevent, diagnose, ortreat such medical disorders in mammals, optionally in humans.

The compounds or compositions of the present disclosure are administeredin therapeutically effective amounts. As used herein, an “effectiveamount” of the antibody is a dosage which is sufficient to reduce theactivity of GDF proteins to achieve a desired biological outcome (e.g.,increasing muscle mass or strength). Generally, a therapeuticallyeffective amount may vary with the subject's age, condition, and sex, aswell as the severity of the medical condition in the subject. The dosagemay be determined by a physician and adjusted, as necessary, to suitobserved effects of the treatment. Generally, the compositions areadministered so that compounds are given at a dose between 1 μg/kg and20 mg/kg. Optionally, the compounds are given as a bolus dose, tomaximize the circulating levels of compounds for the greatest length oftime after the dose. Continuous infusion may also be used after thebolus dose.

The methods of treating, diagnosing, or preventing the above medicalconditions with the presently disclosed compounds can also be used onother proteins in the TGF-β superfamily. Many of these proteins, e.g.,BMP-11, are related in structure to GDF-8. Accordingly, in anotherembodiment, the disclosure comprises methods of treating theaforementioned disorders by administering to a subject a compoundcapable of inhibiting BMP-11 or activin, either alone or in combinationwith other TGF-β inhibitors, such as a neutralizing antibody againstGDF-8.

Accordingly, in one aspect, the disclosure. In provides methods forinhibiting GDF-8 in a cell comprising contacting the cell with aneffective amount of a compound or pharmaceutically acceptable salt offormula (I) or (II) or any embodiment thereof, or a pharmaceuticalcomposition comprising the same. In another aspect, the disclosurecomprises methods for treating a patient suffering from a disease ordisorder, wherein the patient would therapeutically benefit from anincrease in mass or strength of muscle tissue, comprising administeringto a patient a therapeutically effective amount of a compound orpharmaceutically acceptable salt of formula (I) or (II) or anyembodiment thereof, or a pharmaceutical composition comprising the same.The disease or disorder can be a muscular disorder, adipose tissuedisorder, neuromuscular disorders, metabolic disorder, diabetes, or bonedegenerative disorder. In certain embodiments, the disease or disorderis a muscular disorder, such as, but not limited to, muscular dystrophy,muscle atrophy, congestive obstructive pulmonary disease, muscle wastingsyndrome, sarcopenia, or cachexia. In certain other embodiments, thedisease or disorder is muscular dystrophy. In other embodiments, thedisease or disorder is obesity, type 2 diabetes, impaired glucosetolerance, syndrome X, insulin resistance induced by trauma, orosteoporosis. In particular embodiments, the disease or disorder isosteoporosis.

In yet other embodiments, the disease or disorder is low bone mass dueto chronic glucocorticoid therapy, premature gonadal failure, androgensuppression, vitamin D deficiency, secondary hyperparathyroidism,nutritional deficiencies, and anorexia nervosa.

In another aspect, the disclosure comprises methods for increasingmuscle mass in a mammal comprising administering a therapeuticallyeffective amount of a compound or pharmaceutically acceptable salt offormula (I) or (II) or any embodiment thereof, or a pharmaceuticalcomposition comprising the same. In another aspect, the disclosurecomprises methods for increasing muscle strength in a mammal comprisingadministering a therapeutically effective amount of a compound orpharmaceutically acceptable salt of formula (I) or (II) or anyembodiment thereof, or a pharmaceutical composition comprising the same.In another aspect, the disclosure comprises methods for increasingtrabecular bone density in a patient in need thereof, comprisingadministering a therapeutically effective amount of a compound orpharmaceutically acceptable salt of formula (I) or (II) or anyembodiment thereof, or a pharmaceutical composition comprising the same.In any of the preceding methods and embodiments, thereof, the subjectcan be a mammal. As used herein, the terms“individual” or “patient” or“subject” are used interchangeably, and refers to any animal, includingmammals, preferably mice, rats, other rodents, rabbits, dogs, cats,swine, cattle, sheep, horses, or primates, and most preferably humans.

Pharmaceutical Formulations and Dosage Forms

The pharmaceutical compositions described herein generally comprise acombination of a compound described herein and a pharmaceuticallyacceptable carrier, diluent, or excipient. Such compositions aresubstantially free of non-pharmaceutically acceptable components, i.e.,contain amounts of non-pharmaceutically acceptable components lower thanpermitted by US regulatory requirements at the time of filing thisapplication. In some embodiments of this aspect, if the compound isdissolved or suspended in water, the composition further optionallycomprises an additional pharmaceutically acceptable carrier, diluent, orexcipient. In other embodiments, the pharmaceutical compositionsdescribed herein are solid pharmaceutical compositions (e.g., tablet,capsules, etc.).

These compositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

Also, pharmaceutical compositions can contain, as the active ingredient,one or more of the compounds described herein above in combination withone or more pharmaceutically acceptable carriers. In making thecompositions described herein, the active ingredient is typically mixedwith an excipient, diluted by an excipient or enclosed within such acarrier in the form of, for example, a capsule, sachet, paper, or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein. When referring to these preformulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of acompound described herein.

The tablets or pills can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permit the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

The liquid forms in which the compounds and compositions can beincorporated for administration orally or by injection include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds can vary according to, forexample, the particular use for which the treatment is made, the mannerof administration of the compound, the health and condition of thepatient, and the judgment of the prescribing physician. The proportionor concentration of a compound described herein in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, the compounds described herein can beprovided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

The compounds described herein can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

DEFINITIONS

As is understood by those of skill in the art, compounds of the formulaepresented herein, such as but not limited to formula I above, may haveasymmetric centers and accordingly include stereoisomeric forms (e.g.,enantiomers, diastereomers, etc.) of compounds. And in additioncompounds of the formulae presented herein encompass pharmaceuticallyacceptable salts, solvates, for example hydrates, and the like havingsuch formulae. Likewise, the term “compound” as used herein isunderstood to include pharmaceutically acceptable salts, solvates,hydrates and the like of such compounds.

Terms used herein may be preceded and/or followed by a single dash, “—”,or a double dash, “═”, to indicate the bond order of the bond betweenthe named substituent and its parent moiety; a single dash indicates asingle bond and a double dash indicates a double bond or a pair ofsingle bonds in the case of a spiro-substituent. In the absence of asingle or double dash it is understood that a single bond is formedbetween the substituent and its parent moiety; further, substituents areintended to be read “left to right” unless a dash indicates otherwise.For example, C₁-C₆alkoxycarbonyloxy and —OC(O)C₁-C₆alkyl indicate thesame functionality; similarly arylalkyl, arylalkyl-, and alkylarylindicate the same functionality.

Further, certain terms herein may be used as both monovalent anddivalent linking radicals as would be familiar to those skilled in theart, and by their presentation linking between two other moieties. Forexample, an alkyl group can be both a monovalent radical or divalentradical; in the latter case, it would be apparent to one skilled in theart that an additional hydrogen atom is removed from a monovalent alkylradical to provide a suitable divalent moiety.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons, unless otherwise specified,and containing at least one carbon-carbon double bond. Representativeexamples of alkenyl include, but are not limited to, ethenyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,2-heptenyl, 2-methyl-1-heptenyl, 3-dec enyl, and3,7-dimethylocta-2,6-dienyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms, unless otherwisespecified. Representative examples of alkyl include, but are not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl. When an “alkyl” group is a linking group between two othermoieties, then it may also be a straight or branched chain; examplesinclude, but are not limited to —CH₂—, —CH₂CH₂—, —CH₂CH₂CHC(CH₃)—,—CH₂CH(CH₂CH₃)CH₂—.

The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl),or a bicyclic ring system containing at least one phenyl ring or anaromatic bicyclic ring containing only carbon atoms in the aromaticbicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or aphenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or amonocyclic heterocyclyl. The bicyclic aryl is attached to the parentmolecular moiety through any carbon atom contained within the phenylportion of the bicyclic system, or any carbon atom with the napthyl orazulenyl ring. The fused monocyclic cycloalkyl or monocyclicheterocyclyl portions of the bicyclic aryl are optionally substitutedwith one or two oxo and/or thia groups. Representative examples of thebicyclic aryls include, but are not limited to, azulenyl, naphthyl,dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl,dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl,2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl,inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl,dihydronaphthalen-4-yl, dihydronaphthalen-1-yl,5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzo furan-5-yl,2,3-dihydrobenzo furan-6-yl, 2,3-dihydrobenzo furan-7-yl,benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl,2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl,2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl,isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl,inden-1-on-6-yl, inden-1-on-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl,2,3-dihydrobenzo[b][1,4]dioxan-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-5-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-6-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-7-yl,2H-benzo[b][1,4]oxazin3 (4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl,benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl,benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4 (3H)-on-5-yl,quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl,quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl,quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl,quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl,benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and,benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic arylis (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 memberedmonocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl,cycloalkenyl, and heterocyclyl groups are optionally substituted withone or two groups which are independently oxo or thia.

The term “arylalkyl,” “-alkylaryl,” and “arylalkyl-” as used herein,means an aryl group, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein. Representativeexamples of arylalkyl include, but are not limited to, benzyl,2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

The terms “cyano” and “nitrile” as used herein, mean a —CN group.

The term “cycloalkyl” as used herein, means a monocyclic or a bicycliccycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbongroups containing from 3 to 8 carbon atoms, where such groups can besaturated or unsaturated, but not aromatic. In certain embodiments,cycloalkyl groups are fully saturated. Examples of monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicycliccycloalkyl ring systems are bridged monocyclic rings or fused bicyclicrings. Bridged monocyclic rings contain a monocyclic cycloalkyl ringwhere two non-adjacent carbon atoms of the monocyclic ring are linked byan alkylene bridge of between one and three additional carbon atoms(i.e., a bridging group of the form —(CH₂), —, where w is 1, 2, or 3).Representative examples of bicyclic ring systems include, but are notlimited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain amonocyclic cycloalkyl ring fused to either a phenyl, a monocycliccycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or amonocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl isattached to the parent molecular moiety through any carbon atomcontained within the monocyclic cycloalkyl ring. Cycloalkyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a5 or 6 membered monocyclic cycloalkyl ring fused to either a phenylring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 memberedmonocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a5 or 6 membered monocyclic heteroaryl, wherein the fused bicycliccycloalkyl is optionally substituted by one or two groups which areindependently oxo or thia.

“Cycloalkenyl” as used herein refers to a monocyclic or a bicycliccycloalkenyl ring system. Monocyclic ring systems are cyclic hydrocarbongroups containing from 3 to 8 carbon atoms, where such groups areunsaturated (i.e., containing at least one annular carbon-carbon doublebond), but not aromatic. Examples of monocyclic ring systems includecyclopentenyl and cyclohexenyl. Bicyclic cycloalkenyl rings are bridgedmonocyclic rings or a fused bicyclic rings. Bridged monocyclic ringscontain a monocyclic cycloalkenyl ring where two non-adjacent carbonatoms of the monocyclic ring are linked by an alkylene bridge of betweenone and three additional carbon atoms (i.e., a bridging group of theform —(CH₂), —, where w is 1, 2, or 3). Representative examples ofbicyclic cycloalkenyls include, but are not limited to, norbornenyl andbicyclo[2.2.2]oct-2-enyl. Fused bicyclic cycloalkenyl ring systemscontain a monocyclic cycloalkenyl ring fused to either a phenyl, amonocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicycliccycloalkenyl is attached to the parent molecular moiety through anycarbon atom contained within the monocyclic cycloalkenyl ring.Cycloalkenyl groups are optionally substituted with one or two groupswhich are independently oxo or thia.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. In certain examples, a haloalkyl can compriseone to five halogen atoms, or one to three halogen atoms. Representativeexamples of haloalkyl include, but are not limited to, chloromethyl,2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic ring system containing at least one heteroaromatic ringwherein the heteroatom(s) are selected from O, N, and S. The monocyclicheteroaryl can be a 5 or 6 membered ring. The 5 membered ring consistsof two double bonds and one, two, three or four nitrogen atoms andoptionally one oxygen or sulfur atom. The 6 membered ring consists ofthree double bonds and one, two, three or four nitrogen atoms. The 5 or6 membered heteroaryl is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within theheteroaryl. Representative examples of monocyclic heteroaryl include,but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and triazinyl. The bicyclic heteroaryl consists of amonocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, amonocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclicheteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclicheteroaryl group is optionally substituted with one or two groups whichare independently oxo or thia. When the bicyclic heteroaryl contains afused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclicheteroaryl group is connected to the parent molecular moiety through anycarbon or nitrogen atom contained within the monocyclic heteroarylportion of the bicyclic ring system. When the bicyclic heteroaryl is amonocyclic heteroaryl fused to a phenyl ring or a monocyclic heteroaryl,then the bicyclic heteroaryl group is connected to the parent molecularmoiety through any carbon atom or nitrogen atom within the bicyclic ringsystem. Representative examples of bicyclic heteroaryl include, but arenot limited to, benzimidazolyl, benzofuranyl, benzothienyl,benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl,5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl,indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl,5,6,7,8-tetrahydro quinolin-2-yl, 5,6,7,8-tetrahydro quinolin-3-yl,5,6,7,8-tetrahydro quinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl,thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments,the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroarylring fused to either a phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia.

The term “heteroarylalkyl” and “-alkylheteroaryl” as used herein, meansa heteroaryl, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Such groups are indicatedherein subgenerically for example by “heteroaryl(C₁₋₆alkyl) to indicatea heteroaryl moiety linked to the parent molecule through a C₁₋₆alkylgroup, such as a methylene, ethylene, propylene moiety or the like.Representative examples of heteroarylalkyl include, but are not limitedto, fur-3-ylmethyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl,1-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl,pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, andthien-3-ylmethyl.

The term “heterocyclyl” as used herein, means a monocyclic heterocycleor a bicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or7 membered ring containing at least one heteroatom independentlyselected from the group consisting of O, N, and S where the ring issaturated or unsaturated, but not aromatic. The 3 or 4 membered ringcontains 1 heteroatom selected from the group consisting of O, N and S.The 5 membered ring can contain zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. The6 or 7 membered ring contains zero, one or two double bonds and one, twoor three heteroatoms selected from the group consisting of O, N and S.The monocyclic heterocycle is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within themonocyclic heterocycle. Representative examples of monocyclicheterocycle include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, andtrithianyl. The bicyclic heterocycle is a monocyclic heterocycle fusedto either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl,a monocyclic heterocycle, or a monocyclic heteroaryl. The bicyclicheterocycle is connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the monocyclicheterocycle portion of the bicyclic ring system. Representative examplesof bicyclic heterocyclyls include, but are not limited to,2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl,indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl,decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, andoctahydrobenzofuranyl. Heterocyclyl groups are optionally substitutedwith one or two groups which are independently oxo or thia. In certainembodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclicheterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the bicyclic heterocyclyl is optionally substituted by one ortwo groups which are independently oxo or thia.

The term “hydroxy” as used herein, means an —OH group.

The term “nitro” as used herein, means a —NO₂ group.

The term “oxo” as used herein means a ═O group.

The term “saturated” as used herein means the referenced chemicalstructure does not contain any multiple carbon-carbon bonds. Forexample, a saturated cycloalkyl group as defined herein includescyclohexyl, cyclopropyl, and the like.

The term “thia” as used herein means a ═S group.

The term “unsaturated” as used herein means the referenced chemicalstructure contains at least one multiple carbon-carbon bond, but is notaromatic. For example, a unsaturated cycloalkyl group as defined hereinincludes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a kinase with a compound includes theadministration of a compound described herein to an individual orpatient, such as a human, having the kinase (such as Alk4 or Alk5), aswell as, for example, introducing a compound into a sample containing acellular or purified preparation containing the kinase.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

In certain embodiments, a therapeutically effective amount can be anamount suitable for (1) preventing the disease; for example, preventinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease; (2) inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder; or (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

As used here, the terms “treatment” and “treating” means (i)ameliorating the referenced disease state, for example, ameliorating adisease, condition or disorder in an individual who is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing or improving the pathology and/orsymptomatology) such as decreasing the severity of disease; (ii)eliciting the biological or medicinal response that is being sought in atissue, system, animal, individual or human by a researcher,veterinarian, medical doctor or other clinician; or (iii) inhibiting thereferenced disease state; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder.

As used herein, the phrase “pharmaceutically acceptable salt” refers toboth pharmaceutically acceptable acid and base addition salts andsolvates. Such pharmaceutically acceptable salts include salts ofinorganic and organic acids. Examples of inorganic salts include,without limitation, those formed from hydrochloric, phosphoric,hydrobromic, sulfuric, sulfinic and hydroiodicacids. Examples of organicacids suitable for the formation of pharmaceutically acceptable salts ofthe presently disclosed compounds include acetic, formic, fumaric,glutaric, glycolic, trifluoroacetic, benzenesulfonic, ethanesulfonic,toluenesulfonic, methanesulfonic, nitric, benzoic, camphor sulfonic,citric, cinnamic, oxalic, tartaric, maleic, malonic, mandelic, pamoic,propionic, pyruvic and xinafoic acids, and the like. Non-toxicpharmaceutical base addition salts include salts formed from bases withinorganic and organic counterions. By way of example suitable inorganiccounterions include sodium, potassium, calcium, ammonium, sulfate andthe like. Pharmaceutically acceptable organic bases for the formation ofbase addition salts include, without limitation, arginine, choline,ethylenediamine, histidine, lysine, methylglucamine, piperazine,triethanolamine and tris(hydroxymethyl)aminomethane (tris). Thoseskilled in the art will recognize a wide variety of non-toxicpharmaceutically acceptable addition salts. For additionalpharmaceutically acceptable salts, see, M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19 which isincorporated herein by reference.

EXAMPLES

The following abbreviations and/or acronyms are used within theexamples:

Ph Phenyl DMF N,N-dimethylformamide aq. Aqueous dppf 1,1′- MW microwaveBis(diphenylphosphino)- ferrocene LC/MS Liquid chromatograph, HPLCHigh-performance liquid or LCMS mass spectrometry chromatography TFATrifluoroacetic acid DMA N,N-dimethylacetamide EtOAc Ethyl acetate EtOHEthanol MeOH Methanol dba dibenzylideneacetone DMSO Dimethylsulfoxide MeMethyl Et Ethyl Ac2O Acetic anhydride TLC Thin layer OAc acetatechromatography HBTU O-Benzotriazole-N,N,N′,N′- THF Tetrahydrofurantetramethyl-uronium- rt Room temperature DMAP 4-dimethylaminopyridinehexafluoro-phosphate iPr₂NEt di(isopropyl)ethylamine t-BuOMe Tert-butylmethyl ether NBS N-bromosuccinimide AcOH Acetic acid

Example 1 General Synthetic Scheme A

Example 2 General LC/MS Methods

LC/MS: room temperature (A or B)

Method A: Column: Luna 5μ C8 (100×4.6 mm), Flow rate 1.0 ml/min, Mobilephase:A:H₂O 0.05% TFA, B: CH₃CN 0.05% TFA

Method B: Column: Gemini 5μ C18 (100×4.6 mm), Flow rate 1.5 ml/min,Mobile phase:A:H₂O 0.05% HCOOH, B: CH₃CN 0.05% HCOOH

Example 3 5-(2-Chloropyridin-3-yl)-1H-indazole

A single necked round bottom flask equipped with a magnetic stir bar wascharged with 1-Boc-indazole-5-boronic acid pinacol ester (3.0 g, 8.7mmol), 3-bromo-2-chloropyridine (2.0 g, 10.4 mmol), Pd(PPh₃)₄ (1 g, 0.86mmol) and 2M aq. Na₂CO₃ (10 mL, 20 mmol) and 1,4-dioxane under nitrogenatmosphere. The reaction flask was fitted with a reflux condensercontaining three-way stopcock equipped with argon filled balloon. Thereaction contents were stirred and air was removed from the closedreaction system by vacuum and back filled with argon. Following threecycles of degassing, the reaction mixture was heated at 100° C.(oil-bath) under argon. Initial clear heterogeneous reaction mixtureturned to clear biphasic off-yellow solution. After 12 h with noadditional change in the proportion of the product, as analyzed byLC/MS, the reaction mixture was cooled to room temperature. Uponconcentration of the reaction mixture, EtOAc/water (200 mL/100 mL) wastransferred to the concentrate and stirred for 30 min. The organic layerwas separated and the aqueous layer extracted with EtOAc (2×75 mL).MgSO₄ and Celite® were added to combined organic layers, stirred for 20min and the contents suction filtered. The filter cake was washed withEtOAc (100 mL) and the combined filtrates concentrated by rotaryevaporator under vacuum. The crude concentrate was dissolved in in 1%MeOH/CH₂Cl₂ and absorbed on silica gel (20 g) by evaporating the solventfollowed by drying. Subsequent purification by flash silica gel columnpurification of the dry powder (Combiflash® Companion System® withRediSep® silica gel column 120 g, 30-70% EtOAc/hexanes eluting solvent)provided 5-(2-chloropyridin-3-yl)-1H-indazole (1.0 g, 50%) as a whitecrystalline solid after concentration of the desired product fractions.¹H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.41 (dd, 1H, J=1.8 and 4.7 Hz), 8.13(s, 1H), 7.90 (dd, 1H, J=1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H,J=8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.3 Hz), 7.42 (dd, 1H, J=1.4 and 8.5Hz). LCMS: 95%, MS (m/e) 230 (MH⁺).

Example 4 tert-Butyl 5-bromo-1H-indazole-1-carboxylate

A single necked round bottom flask containing a with a magnetic stir barwas charged with 5-bromo-1H-indazole (3.0 g, 15.2 mmol), di-tert-butyldicarbonate (4.2 g, 19.2 mmol) and acetonitrile (30 mL) under a mildstream of nitrogen at room temperature. Triethylamine (1.8 g, 2.5 mL,17.7 mmol) was added in one portion to the above stirred homogeneoussolution followed by portions-wise addition of 4-(dimethylamino)pyridine(2.2 g, 18 mmol) over a period of 15 min. The homogenous off-brown clearreaction mixture was stirred at room temperature under nitrogen and theprogress of reaction monitored by TLC (50% EtOAc/hexanes). Stirring wasdiscontinued after 3h and the reaction mixture concentrated by rotaryevaporator under vacuum. A clear viscous liquid was obtained anddissolved in EtOAc/hexanes (7:3, 200 mL), and diluted with water (75mL). Organic layer was separated and the aqueous layer extracted withEtOAc/hexanes (1:1, 125 mL). The combined organic layers were washedwith water (100 mL) followed by 1N aq. HCl (2×75 mL) to remove4-(dimethylamino)pyridine. The combined organic layers were washed withwater (2×75 mL), saturated aq. NaHCO₃ (2×75 mL) and saturated aqueousNaCl. Separated organic layers were dried over anhydrous MgSO₄,filtered, concentrated and dried under vacuum to provide tert-butyl5-bromo-1H-indazole-carboxylate (4.5 g, purity 97%) as a pale yellowviscous liquid which was used without further purification. ¹H NMR(DMSO-d6): δ 8.36 (d, 1H, J=0.8 Hz), 8.11 (app d, 1H, J=0.8 Hz), 8.00(d, 1H, J=8.8 Hz), 7.71 (app dd, 1H, J=0.8 and 8.8 Hz), 1.62 (s, 9H).LCMS: 97%, MS (m/e) 241 (MH⁺-t-Bu).

Example 5 5-(2-Chloropyridin-3-yl)-1H-indazole

A single necked round bottom flask (250 mL) equipped with a magneticstir bar was charged with tert-butyl 5-bromo-1H-indazole-carboxylate(4.0 g, 13.4 mmol) dissolved in 1,4-dioxane (130 mL),2-chloro-3-pyridine boronic acid pinacol ester (4 g, 16.7 mmol),Pd(PPh₃)₄ (1.5 g, 1.3 mmol) and 2M aq.Na₂CO₃ (20 mL, 40 mmol) undernitrogen atmosphere. The rubber septum was replaced with refluxcondenser containing three-way stopcock equipped with argon filledballoon. The reaction contents were stirred and air was removed from theclosed reaction system by vacuum and back filled with argon. Followingthree cycles of degassing, the reaction mixture was heated at 100° C.(oil-bath) under argon. Inflated argon balloon was emptied, refilledwith argon and remounted in the course of reaction. The initial paleyellow heterogeneous reaction mixture turned to clear biphasic off-brownsolution. After 18 h with no additional change in the proportion of theproduct (62%) as analyzed by LC/MS, the reaction mixture was cooled toroom temperature. Upon concentration of the reaction mixture,EtOAc/water (200 mL/75 mL) was transferred to the concentrate andstirred for 30 min. The organic layer was separated and the aqueouslayer extracted with EtOAc (100 mL×2). MgSO₄ (20 g) and Celite® (20 g)were added to combined organic layers and the contents suction filteredafter stirring for 1 h. The filter cake was washed with EtOAc (300 mL)and the combined filtrates concentrated by rotary evaporator undervacuum. The crude concentrate was dissolved in in 1% MeOH/CH₂Cl₂ andabsorbed on silica gel (20 g) by evaporating the solvent followed bydrying. Subsequent purification by flash silica gel column purificationof the dry powder (Combiflash® companion System® with RediSep® silicagel column 120 g, 30-70% EtOAC/hexanes eluting solvent) provided5-(2-chloropyridin-3-yl)-1H-indazole (1.5 g, 47%) as a white crystallinesolid after concentration of the desired product fractions. ¹H NMR(DMSO-d6): δ 13.2 (s, 1H), 8.41 (dd, 1H, J=1.8 and 4.7 Hz), 8.13 (s,1H), 7.90 (dd, 1H, J=1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J=8.8Hz), 7.51 (dd, 1H, J=4.7 and 7.3 Hz), 7.42 (dd, 1H, J=1.4 and 8.5 Hz).LCMS: 95%, MS (m/e) 230 (MH⁺).

Example 6 tert-Butyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate

A single necked round bottom flask equipped with a magnetic stir bar wascharged with 5-bromo-1H-pyrazolo[3,4-b]pyridine (1.0 g, 5 mmol),di-tert-butyl dicarbonate (1.4 g, 6.4 mmol) and acetonitrile (10 mL)under a mild stream of nitrogen at room temperature. Triethylamine (0.72g, 1.0 mL, 7.1 mmol) was added in one portion to the above stirredhomogeneous solution followed by portions-wise addition of4-(dimethylamino)pyridine (0.74 g, 6.05 mmol) over a period of 15 min.The homogenous reaction mixture was stirred at room temperature and theprogress of reaction was monitored by TLC (50% EtOAc/hexanes). Stirringwas discontinued after 3h, the reaction mixture concentrated and dilutedwith water (25 mL). The resultant off-brown solid was filtered andsuction dried to provide the desired tert-butyl5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (1.4 g, 93%). Thematerial obtained was used in the next step without furtherpurification. ¹H NMR (DMSO-d6): δ 8.77 (d, 1H, J=2.0 Hz), 8.62 (d, 1H,J=2.0 Hz), 8.39 (s, 1H), 1.60 (s, 9H), (dd, 1H, J=1.8 and 4.7 Hz), 8.13(s, 1H), 7.90 (dd, 1H, J=1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H,J=8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.3 Hz), 7.42 (dd, 1H, J=1.4 and 8.5Hz). LCMS: 97%, MS (m/e) 226 (MH⁺-t-Bu).

Example 7 5-(2-Chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine

5-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine was prepared in thesimilar to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole byheating the mixture of tert-butyl5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (2.0 g, 6.7 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.9 g, 8.0 mmol),Pd(PPh₃)₄ (770 mg, 67 mmol), 1,4-dioxane (40 mL) and 2M aq.Na₂CO₃ (9 mL,18 mmol) under argon atmosphere. After 12 h, the reaction mixture wascooled to room temperature and concentrated. The crude concentrate wasdiluted with EtOAc/water (200 mL/100 mL), allowed to stir for 30 min andthe heterogeneous solution was filtered. The filter cake was washed withEtOAc (200 mL) and water (75 mL) successively. The filter cake thusobtained was analyzed as the desired product (0.55 g) and dissolved in amixture of THF/MeOH (2:1, 50 mL). The homogeneous solution was passedthrough a pad of Celite® and the filtrate concentrated to providedesired product as a crystalline solid (0.45 g). Organic layer fromcombined filtrates was separated, stirred with MgSO₄/Celite® for 20 minand filtered. The filtrate was concentrated and subjected to flashsilica gel column purification (Combiflash® companion System® withRediSep® silica gel column 12g, 30-50-90EtOAC/hexanes eluting solventgradient upon dry loading the sample by absorbing on silica gel) toobtain another 0.4 g of5-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine. Total yield: 52%.¹H NMR (DMSO-d6): δ 13.83 (s, 1H), 8.59 (d, 1H, J=2.0 Hz), 8.45 (dd, 1H,J=1.7 and 4.7 Hz), 8.36 (d, 1H, J=2.0 Hz), 8.21 (s, 1H), 8.00 (dd, 1H,J=1.7 and 7.7 Hz), 7.59 (dd, 1H, J=4.7 and 7.7 Hz). LCMS: rt 5.20 min(A), purity 94%, MS (m/e) 231 (MH⁺).

Example 8 2-Chloro-3-(4-fluorophenyl)pyridine

2-Chloro-3-(4-fluorophenyl)pyridine was synthesized analogous to thereaction conditions used in the preparation of5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of4-fluorophenyl boronic acid (3.0 g, 21.4 mmol), 3-bromo-2-chloropyridine(4.9 g, 25.7 mmol), Pd(PPh₃)₄ (1.6 g, 1.3 mmol) and 2M aq. Na₂CO₃ (25mL, 50 mmol) in 1,4-dioxane (125 mL) under argon atmosphere for 12 h.LC/MS indicated three products with MH⁺208, 254 and 268. Upon work-up ofthe reaction mixture, as discussed in the preparation of5-(2-chloropyridin-3-yl)-1H-indazole, the crude concentrated waspurified by flash silica gel column chromatography [Combiflash®Companion System® with RediSep® silica gel column 120 g, 10-50%EtOAC/hexanes eluting solvent gradient upon liquid loading on tocolumn]. Two fractions containing the desired product were identifiedand concentrated. 2-Chloro-3-(4-fluorophenyl)pyridine was isolated as acrystalline solid (888 mg, 16%) from the fraction containing2,3-bis(4-fluorophenyl)pyridine by suspending the semi solid fractionmixture in 10% EtOAc/hexanes and filtered. ¹H NMR (DMSO-d6): δ 8.41 (dd,1H, J=1.8 and 4.7 Hz), 7.86 (dd, 1H, J=2.0 and 7.6 Hz), 7.54-7.48 (m,3H), 7.34-7.31 (m, 2H). ¹⁹F NMR (DMSO-d6): δ −114.06 (s). LCMS: rt 7.50min (A), purity 99%, MS (m/e) 208 (MH⁺).

Example 9 tert-Butyl 6-bromo-1H-indazole-1-carboxylate

Analogous to the preparation and work-up procedure often-butyl5-bromo-1H-indazole-carboxylate, tert-butyl6-bromo-1H-indazole-carboxylate was obtained by the reaction of6-bromo-1H-indazole (5.0 g, 25.4 mmol), di-tert-butyl dicarbonate (7.2g, 32.9 mmol), triethylamine (3.6 g, 1.0 mL, 35.7 mmol) and4-(dimethylamino)pyridine (3.1 g, 25 mmol) in acetonitrile (40 mL) undera mild stream of nitrogen at room temperature. tert-butyl6-bromo-1H-indazole-carboxylate (7.5 g, 97%) as a pale yellow viscousliquid which was used without further purification. ¹H NMR (DMSO-d6): δ8.36 (d, 1H, J=0.8 Hz), 8.11 (app d, 1H, J=0.8 Hz), 8.00 (d, 1H, J=8.8Hz), 7.71 (app dd, 1H, J=0.8 and 8.8 Hz), 1.62 (s, 9H). LCMS: 97%, MS(m/e) 241 (MH⁺-t-Bu).

Example 10 6-(2-Chloropyridin-3-yl)-1H-indazole

Analogous to the reaction conditions and work-up procedures used in thepreparation of 5-(2-chloropyridin-3-yl)-1H-indazole,5-(2-chloropyridin-3-yl)-1H-indazole was obtained by heating the mixtureof tert-butyl 6-bromo-1H-indazole-carboxylate (7.3 g, 24.6 mmol),2-chloro-3-pyridine boronic acid pinacol ester (7.0 g, 29.5 mmol),Pd(PPh₃)₄ (2 g, 1.7 mmol) and aq.Na₂CO₃ (44 mL, 88 mmol) in 1,4-dioxane(200 mL) under argon atmosphere. The crude concentrate that was obtainedafter the extractive work-up dissolved in CH₂Cl₂, adsorbed on to silicagel and dried. Subsequent purification by flash silica gel columnchromatography (Combiflash® Companion System® with RediSep® silica gelcolumn 120 g, 30-70% EtOAC/hexanes eluting solvent gradient upon drypowder loading) provided 5-(2-chloropyridin-3-yl)-1H-indazole as a whitesolid (4.2 g, 74%). ¹H NMR (DMSO-d6): δ 13.21 (s, 1H), 8.43 (dd, 1H,J=1.7 and 4.7 Hz), 8.12 (s, 1H), 7.93 (dd, 1H, J=1.7 and 7.6 Hz), 7.84(d, 1H, J=8.5 Hz), 7.59 (s, 1H), 7.52 (dd, 1H, J=4.7 and 7.6 Hz), 7.17(d, 1H, J=8.5 Hz). LCMS: rt 6.17 min (A), purity 98%, MS (m/e) 230(MH⁺).

Example 11 1-Trityl-6-bromo-2-benzoxazilinone

Triethylamine (0.72 g, 1.0 mL, 7.1 mmol) was added to a stirring amixture of 6-bromo-2benzoxazilinone (0.89 g, 4.2 mmol) andtritylchloride (1.21 g, 4.4 mmol) in CH₂Cl₂ (10 mL) for a period of 10min. The reaction was monitored by TLC (silica gel) and concentratedafter 1 h. The concentrate was diluted with water and sonicated to forma heterogeneous solution. The resulting off-white solid was suctionfiltered and dried to provide 1-trityl-6-bromo-2-benzoxazilinone (2.0g). LCMS: rt 9.45 min (A), purity 96%, MS (m/e) 456 (MH⁺).

Example 12 6-(2-chloropyridin-3-yl)benzo[d]oxazol-2(3H)-one

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,6-(2-chloropyridin-3-yl)benzo[d]oxazol-2(3H)-one was prepared by heatingthe mixture of 1-trityl-6-bromo-2-benzoxazilinone (2.0 g, 4.4 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.3 g, 5.4 mmol),Pd(PPh₃)₄ (0.5 g, 0.43 mmol) and 2M aq. Na₂CO₃ (8 mL, 16 mmol) in1,4-dioxane (75 mL) under argon atmosphere for 12 h. LC/MS indicatedthree products with MH⁺ 489, 245 and 566. Extractive work-up followed byflash silica gel column purification (Combiflash® companion System® withRediSep® silica gel column 40 g, 20-70% EtOAC/hexanes eluting solventgradient upon dry loading the concentrate absorbed on silica gel)provided 6-(2-chloropyridin-3-yl)benzo[d]oxazol-2(3H)-one (0.44 g, 38%)as an off-white solid after concentration of the respective productfractions. LCMS: rt 5.85 min (A), purity 94%, MS (m/e) 247 (MH⁺).

Example 13 3-(Benzo[d][1,3]dioxol-6-yl)-2-chloropyridine

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,3-(benzo[d][1,3]dioxol-6-yl)-2-chloropyridine was prepared by heatingthe mixture of 3,4-(methylenedioxy)phenyl boronic acid (3.0 g, 18.1mmol), 3-bromo-2-chloropyridine (4.2 g, 1.8 mmol), Pd(PPh₃)₄ (1.2 g, 1.0mmol) and 2M aq. Na₂CO₃ (27 mL, 54 mmol) in 1,4-dioxane (125 mL) underargon atmosphere for 12 h. LC/MS indicated three products. The crudeconcentrate that was obtained after the extractive work-up dissolved inCH₂Cl₂, adsorbed on to silica gel and dried. Subsequent purification byflash silica gel column chromatography (Combiflash® companion System®with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes elutingsolvent gradient upon dry powder loading) provided3-(benzo[d][1,3]dioxol-6-yl)-2-chloropyridine as a white solid 2.3 g,(38%). ¹H NMR (DMSO-d6): δ 8.38 (dd, 1H, J=1.7 and 4.7 Hz), 7.82 (dd,1H, J=2.0 and 7.6 Hz), 7.47 (dd, 1H, J=4.7 and 7.6 Hz), 7.05 (d, 1H,J=1.7 Hz), 7.01 (d, 1H, J=7.9 Hz), 6.90 (dd, 1H, J=1.7 and 7.9 Hz), 6.07(s, 2H LCMS: rt 7.27 min (A), purity 96%, MS (m/e) 234 (MH⁺).

Example 14 6-(2-Chloropyridin-3-yl)-1-methyl-1H-indazole

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,6-(-2-chloropyridin-3-yl)-1-methyl-1H-indazole was prepared by heatingthe mixture of 6-bromo-1-methyl-1H-indazole (2.0 g, 9.5 mmol),2-chloro-3-pyridine boronic acid pinacol ester (2.2 g, 9.4 mmol),Pd(PPh₃)₄ (0.54 g, 0.46 mmol) and 2M aq. Na₂CO₃ (14 mL, 28 mmol) in1,4-dioxane (75 mL) under argon atmosphere for 12 h. Upon extractivework-up as discussed in the preparation of of5-(2-chloropyridin-3-yl)-1H-indazole with CH₂Cl₂ and purification of theconcentrate by flash silica gel column chromatography (Combiflash®Companion System® with RediSep® silica gel column 40 g, 30-50%EtOAC/hexanes eluting solvent gradient upon dry loading the concentrateabsorbed on silica gel) provided6-(-2-chloropyridin-3-yl)-1-methyl-1H-indazole as a white solid (1.8 g,77%). ¹H NMR (DMSO-d6): δ 8.45 (dd, 1H, J=1.7 and 4.7 Hz), 8.09 (s, 1H),7.94 (dd, 1H, J=2.0 and 7.6 Hz), 7.82 (d, 1H, J=8.5 Hz), 7.74 (s, 1H),7.54 (dd, 1H, J=4.7 and 7.6 Hz), 7.22 (d, 1H, J=8.5 Hz), 4.06 (s, 3H).LCMS: rt 6.80 min (A), purity 97%, MS (m/e) 244 (MH⁺).

Example 15 tert-Butyl 6-bromo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

Analogous to the preparation often-butyl5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate,6-bromo-1H-pyrazolo[4,3-b]pyridine (2.0 g, 10.10 mmol) was reacted withdi-tert-butyl dicarbonate (2.8 g, 13.10 mmol), NEt₃ (1.44 g, 2.0 mL, 14mmol) and 4-(dimethylamino)pyridine in acetonitrile (20 mL) for 3h.Work-up as discussed previously in the preparation of tert-butyl5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate provided desiredproduct of tert-butyl 6-bromo-1H-pyrazolo[4,3-b]pyridine-1-carboxylateas a brown solid (2.8 g, 93%).

Example 16 6-(2-Chloropyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

6-(2-Chloropyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine was synthesized inthe similar manner to the preparation of5-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine by heating themixture of tert-butyl 6-bromo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(2.5 g, 8.4 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (2.2g, 9.2 mmol), Pd(PPh₃)₄ (610 mg, 0.52 mmol) and 2M aq.Na₂CO₃ (12 mL, 24mmol) in 1,4-dioxane (40 mL). Upon work-up of the reaction mixturesimilar to 5-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine provided6-(2-chloropyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine as an off-whitecrystalline solid. ¹H NMR (DMSO-d6): δ 13.50 (s, 1H), 8.57 (app s, 1H),8.48 (dd, 1H, J=1.7 and 4.7 Hz), 8.35 (s, 1H), 8.12 (s, 1H), 8.02 (dd,1H, J=1.7 and 7.6 Hz), 7.60 (dd, 1H, J=4.7 and 7.7 Hz). LCMS: rt 4.50min (A), purity 94%, MS (m/e) 231 (MH⁺).

Example 17 6-(2-Chloropyridin-3-yl)-1-methyl-1H-indazole

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,5-(2-chloropyridin-3-yl)-1-methyl-1H-indazole was prepared by heatingthe mixture of 5-bromo-1-methyl-1H-indazole (1.0 g, 4.7 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.2 g, 5.2 mmol),Pd(PPh₃)₄ (270 mg, 0.23 mmol) and 2M aq. Na₂CO₃ (6 mL, 12 mmol) in1,4-dioxane (75 mL) under argon atmosphere for 12 h. Upon work-up asdiscussed in the preparation of of 5-(2-chloropyridin-3-yl)-1H-indazoleand purification of the concentrate by flash silica gel columnchromatography [Combiflash® Companion System® with RediSep® silica gelcolumn 40 g, 30-50% EtOAc/hexanes eluting solvent gradient upon dryloading the concentrate absorbed on silica gel] provided5-(2-chloropyridin-3-yl)-1methyl-1H-indazole as white solid (0.84 g,73%). ¹H NMR (DMSO-d6): δ 8.41 (dd, 1H, J=1.7 and 4.7 Hz), 8.10 (s, 1H),7.90 (dd, 1H, J=1.7 and 7.6 Hz), 7.83 (app t, 1H, J=0.6 Hz), 7.72 (dd,1H, J=0.6 and 8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.6 Hz), 7.48 (dd, 1H,J=1.7 and 8.8 Hz), 4.07 (s, 3H). LCMS: rt 6.73 min (A), purity 99%, MS(m/e) 244 (MH⁺).

Example 18 tert-Butyl 5-bromo-3-methyl-1H-indazole-1-carboxylate

Analogous to the preparation tert-butyl5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate, tert-butyl5-bromo-3-methyl-1H-indazole-1-carboxylate was prepared by reacting5-bromo-3-methyl-1H-indazole (1.0g, 4.7 mmol), di-tert-butyl dicarbonate(1.2 g, 6.4 mmol), NEt₃ (0.72g, 1.0 mL, 7.1 mmol) and4-(dimethylamino)pyridine (0.57 g, 4.7 mmol). The reaction mixture wasconcentrated and diluted with water. The resultant solid was collectedby filtration and suction dried to provide tert-butyl5-bromo-3-methyl-1H-indazole-1-carboxylate (1.5 g, 97%) as a whitesolid. ¹H NMR (DMSO-d6): δ 8.10 (d, 1H, J=1.8 Hz), 7.96 (d, 1H, J=9.1Hz), 7.71 (dd, 1H, J=1.8 and 9.1 Hz), 2.49 (s, 3H), 1.61 (s, 9H). LCMS:97%, MS (m/e) 254 (MH⁺-t-Bu).

Example 19 5-(2-Chloropyridin-3-yl)-3-methyl-1H-indazole

5-(2-Chloropyridin-3-yl)-3-methyl-1H-indazole was synthesized in thesimilar manner to the preparation of5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture oftert-butyl 5-bromo-3-methyl-1H-indazole-1-carboxylate (1.5 g, 4.8 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.3 g, 5.3 mmol),Pd(PPh₃)₄ (390 mg, 0.33 mmol) and 2M aq.Na₂CO₃ (7 mL, 14 mmol) in1,4-dioxane (40 mL). Upon work-up and purification procedure used in thepreparation of 5-(2-chloropyridin-3-yl)-1H-indazole provided5-(2-chloropyridin-3-yl)-3-methyl-1H-indazole (0.52, 43%) as a whitecrystalline solid. ¹H NMR (DMSO-d6): δ 12.75 (s, 1H), 8.41 (dd, 1H,J=1.7 and 4.7 Hz), 7.91 (dd, 1H, J=1.7 and 7.6 Hz), 7.77 (s, 1H), 7.52(d, 1H, J=8.5 Hz), 7.51 (dd, 1H, J=4.7 and 7.6 Hz), 7.41 (dd, 1H, J=1.4and 8.5 Hz), 2.49 (s, 3H). LCMS: rt 6.28 min (A), purity 97%, MS (m/e)244.

Example 20 6-(2-Chloropyridin-3-yl)benzo[d]thiazole

6-(2-Chloropyridin-3-yl)benzo[d]thiazole was prepared analogous to5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of6-bromobenzo[d]thiazole (2.0 g, 9.3 mmol), 2-chloro-3-pyridine boronicacid pinacol ester (2.7 g, 11.2 mmol), Pd(PPh₃)₄ (500 mg, 0.43 mmol) and2M aq.Na₂CO₃ (14 mL, 28 mmol) in 1,4-dioxane (100 mL). The reactionmixture was concentrated at the completion of the reaction (12h) anddiluted with CH₂Cl₂ (200 mL/100 mL). Mixed organic layers were stirredwith MgSO₄ and Celite® for 30 min. The slurry was suction filtered andconcentrated by rotary evaporator under vacuum. The crude concentratewas dissolved in CH₂Cl₂, adsorbed on silica gel and dried. The drypowder thus obtained was purified by silica gel flash columnchromatography (Combiflash® Companion System® with RediSep® silica gelcolumn 40 g, 30-70% EtOAC/hexanes eluting solvent gradient).6-(2-chloropyridin-3-yl)benzo[d]thiazole (1.9 g, 82%) was obtained as awhite solid upon concentration of the product fractions. ¹H NMR(DMSO-d6): δ 9.46 (s, 1H), 8.46 (dd, 1H, J=1.7 and 4.7 Hz), 8.30 (d, 1H,J=1.4 Hz), 8.17 (d, 1H, J=8.2 Hz), 7.96 (dd, 1H, J=1.7 and 7.6 Hz), 7.63(dd, 1H, J=1.4 and 8.5 Hz), 7.53 (dd, 1H, J=4.7 and 7.6 Hz). LCMS: rt6.71 min (A), purity 99%, MS (m/e) 247.

Example 21 5-(2-Chloropyridin-3-yl)benzo[d]thiazole

5-(2-chloropyridin-3-yl)benzo[d]thiazole was prepared in the similarmanner of 6-(2-chloropyridin-3-yl)benzo[d]thiazole by heating themixture of 5-bromobenzothiazole (1.0 g, 4.67 mmol), 2-chloro-3-pyridineboronic acid pinacol ester (1.34 g, 5.6 mmol), Pd(PPh₃)₄ (250 mg, 0.22mmol) and 2M aq.Na₂CO₃ (7 mL, 14 mmol) in 1,4-dioxane (50 mL). Uponwork-up and purification protocol used in the preparation of6-(2-chloropyridin-3-yl)benzo[d]thiazole provided5-(2-chloropyridin-3-yl)benzo[d]thiazole as a white solid (820 mg, 70%).¹H NMR (DMSO-d6): δ 9.46 (s, 1H), 8.45 (dd, 1H, J=2.0 and 4.9 Hz), 8.27(d, 1H, J=8.5 Hz), 8.17 (app s, 1H), 7.97 (dd, 1H, J=1.7 and 7.6 Hz),7.58 (d, 1H, J=8.5 Hz), 7.53 (dd, 1H, J=4.7 and 7.6 Hz), LCMS: rt 6.73min (A), purity 99%, MS (m/e) 247.

Example 22 6-(2-Chloropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine

6-(2-chloropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine was synthesizedin the similar to 6-(2-chloropyridin-3-yl)benzo[d]thiazole from6-bromo[1,2,4]triazolo[4,3a]pyridine (1.0 g, 5.0 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.45 g, 6.0 mmol),Pd(PPh₃)₄ (300 mg, 0.26 mmol) and 2M aq.Na₂CO₃ (8 mL, 16 mmol) in1,4-dioxane (50 mL). Workup of the reaction mixture was carried out bysequential steps of concentrating the reaction mixture, extraction withCH₂Cl₂, drying over MgSO₄/Celite®, filtration and concentration. Thusobtained crude residue was dissolved in CH₂Cl₂ (10 mL) and thehomogeneous solution stirred with 50% EtOAc/hexanes (40 mL). Theresulting off-white precipitate was collected by filtration and dried toprovide 6-(2-chloropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (0.68 g,58%). ¹H NMR (DMSO-d6): δ 8.29 (s, 1H), 8.74 (s, 1H), 8.50 (dd, 1H,J=1.7 and 4.7 Hz), 8.01 (dd, 1H, J=1.7 and 7.6 Hz), 7.87 (d, 1H, J=9.7Hz), 7.58 (dd, 1H, J=4.7 and 7.6 Hz), 7.51 (dd, 1H, J=1.4 and 9.7 Hz).LCMS: rt 3.90 min (A), purity 99%, MS (m/e) 231 (MH⁺).

Example 23 6-(2-Chloropyridin-3-yl)imidazo[1,2-a]pyridine

6-(2-Chloropyridin-3-yl)imidazo[1,2-a]pyridine was synthesized in thesimilar to 6-(2-chloropyridin-3-yl)benzo[d]thiazole from6-iodo-imidazo[1,2-a]pyridine (1.0 g, 4.1 mmol), 2-chloro-3-pyridineboronic acid pinacol ester (1.2 g, 5.0 mmol), Pd(PPh₃)₄ (250 mg, 0.22mmol) and 2M aq.Na₂CO₃ (7 mL, 12 mmol) in 1,4-dioxane (50 mL). Workup ofthe reaction mixture was carried out by sequential steps ofconcentrating the reaction mixture, extraction with CH₂Cl₂, drying overMgSO₄/Celite®, filtration and concentration. The crude residue wasstirred in 50% EtOAc/hexanes (40 mL). The resulting white precipitatewas filtered and dried to provide6-(2-chloropyridin-3-yl)imidazo[1,2-a]pyridine (0.52 g, 55%). ¹H NMR(DMSO-d6): δ 8.73 (dd, 1H, J=0.8 and 1.8 Hz), 8.47 (dd, 1H, J=2.0 and4.7 Hz), 8.00 (dd, 1H, J=2.0 and 7.6 Hz), 7.98 (s, 1H), 7.64 (d, 1H,J=8.8 Hz), 7.63 (s, 1H), 7.56 (dd, 1H, J=4.7 and 7.6 Hz), 7.33 (dd, 1H,J=1.8 and 8.8 Hz), Hz). LCMS: rt 3.16 min (A), purity 99%, MS (m/e) 230(MH⁺).

Example 24 tert-Butyl 5-bromo-6-methyl-1H-indazole-1-carboxylate

Analogous to the preparation tert-butyl5-bromo-3-methyl-1H-indazole-1-carboxylate, tert-Butyl5-bromo-6-methyl-1H-indazole-1-carboxylate was prepared by reacting5-bromo-6-methyl-1H-indazole (1.0 g, 4.7 mmol), di-tert-butyldicarbonate (1.2 g, 6.4 mmol), NEt₃ (0.72 g, 1.0 mL, 7.2 mmol) and4-(dimethylamino)pyridine (0.57 g, 4.7 mmol). The reaction mixture wasconcentrated and diluted with water. The resultant precipitate wascollected by filtration to obtain the desired product (1.4 g, 95%). ¹HLCMS: 97%, MS (m/e) (MH⁺-t-Bu).

Example 25 5-(2-Chloropyridin-3-yl)-6-methyl-1H-indazole

5-(2-Chloropyridin-3-yl)-6-methyl-1H-indazole was synthesized in thesimilar manner to the preparation of5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture oftert-butyl 5-bromo-6-methyl-1H-indazole-1-carboxylate (1.4 g, 4.5 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.4 g, 5.9 mmol),Pd(PPh₃)₄ (370 mg, 0.32 mmol) and 2M aq.Na₂CO₃ (7 mL, 14 mmol) in1,4-dioxane (40 mL). Upon work-up and purification procedure used in thepreparation of 5-(2-chloropyridin-3-yl)-1H-indazole provided5-(2-chloropyridin-3-yl)-6-methyl-1H-indazole as a white solid (780 mg,67%). ¹H NMR (DMSO-d6): δ 13.02 (s, 1H), 8.44 (dt, 1H, J=1.7 and 4.7Hz), 8.01 (s, 1H), 7.81 (dt, 1H, J=1.7 and 7.6 Hz), 7.53 (s, 1H),7.51-7.48 (m, 1H), 7.45 (s, 1H), 2.12 (s, 3H). LCMS: rt 6.30 min (A),purity 98%, MS (m/e) 244.

Example 26 tert-Butyl 5-bromo-7-methyl-1H-indazole-1-carboxylate

Analogous to the preparation tert-butyl5-bromo-3-methyl-1H-indazole-1-carboxylate, tert-butyl5-bromo-7-methyl-1H-indazole-1-carboxylate was prepared by reacting5-bromo-7-methyl-1H-indazole (1.0 g, 4.7 mmol), di-tert-butyldicarbonate (1.2 g, 6.4 mmol), NEt₃ (0.72 g, 1.0 mL, 7.2 mmol) and4-(dimethylamino)pyridine (0.57 g, 4.7 mmol). The reaction mixture wasconcentrated, diluted with water (30 mL) and extracted with 50%EtOAc/hexanes (140 mL). Organic layer was washed with aq. 1N HCl, (15mL), water (2×50 mL), aq. NaHCO₃ (2×30 mL) and saturated aq. NaCl (30mL) successively, stirred with MgSO₄, filtered and concentrated toobtain tert-butyl 5-bromo-7-methyl-1H-indazole-1-carboxylate as aviscous liquid. The material thus obtained was used in the next step.

Example 27 5-(2-Chloropyridin-3-yl)-6-methyl-1H-indazole

5-(2-Chloropyridin-3-yl)-7-methyl-1H-indazole was synthesized in thesimilar manner to the preparation of5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture oftert-butyl 5-bromo-6-methyl-1H-indazole-1-carboxylate (1.4 g, 4.5 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.4 g, 5.9 mmol),Pd(PPh₃)₄ (370 mg, 0.32 mmol) and 2M aq.Na₂CO₃ (7 mL, 14 mmol) in1,4-dioxane (40 mL). Upon work-up and purification procedure used in thepreparation of 5-(2-chloropyridin-3-yl)-1H-indazole provided white solidof 5-(2-chloropyridin-3-yl)-7-methyl-1H-indazole (840 mg, 73%). ¹H NMR(DMSO-d6): δ 13.28 (s, 1H), 8.40 (dd, 1H, J=1.7 and 4.7 Hz), 8.11 (appd, 1H, J=1.2 Hz), 7.87 (dd, 1H, J=1.7 and 7.6 Hz), 7.64 (s, 1H), 7.49(dd, 1H, J=4.7 and 7.6 Hz), 7.19 (s, 1H), 2.54 (s, 3H). LCMS: rt 6.41min (A), purity 98%, MS (m/e) 244 (MH⁺).

Example 28 6-(2-Chloropyridin-3-yl)-1H-benzimidazole

6-(2-Chloropyridin-3-yl)-1H-benzimidazole was synthesized in the similarmanner to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole byheating the mixture of 3-bromo-2-chloropyridine (0.70 g, 3.63 mmol),1H-benzimidazole-5-boronic acid pinacol ester (0.8 g, 3.27 mmole),Pd(PPh₃)₄ (330 mg, 0.28 mmol) and 2M aq.Na₂CO₃ (4 mL, 8 mmol) in1,4-dioxane (30 mL). Upon extractive work-up with CH₂Cl₂ andpurification of the concentrate by flash silica gel columnchromatography (Combiflash® Companion System® with RediSep® silica gelcolumn 24 g, 3% MeOH/EtOAc as a eluting solvent upon dry loading theconcentrate absorbed on silica gel) provided6-(2-chloropyridin-3-yl)-1H-benzimidazole (200 mg, 26%). ¹H NMR(DMSO-d6): δ 12.57 (s, 1H), 8.95 (dd, 1H, J=1.7 and 4.9 Hz), 8.28 (s,1H), 7.90 (dd, 1H, J=1.7 and 7.6 Hz), 7.70-7.62 (m, 2H), 7.58 (dd, 1H,J=4.9 and 7.6 Hz), 7.29-7.27 (app s, 1H). LCMS: rt 3.71 min (A), purity96%, MS (m/e) 230 (MH⁺).

Example 29 6-(2-Chloropyridin-3-yl)-1H-benzimidazole

6-(2-Chloropyridin-3-yl)-1-methyl-1H-benzimidazole was synthesized inthe similar manner to the preparation of5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of6-bromo-1-methyl-1H-benzimidazole (1.0 g, 4.7 mmole),2-chloro-3-pyridine boronic acid pinacol ester (1.4 g, 5.8 mmol),Pd(PPh₃)₄ (330 mg, 0.28 mmol) and 2M aq.Na₂CO₃ (7 mL, 14 mmol) in1,4-dioxane (60 mL). Upon extractive work-up with CH₂Cl₂ andpurification (Combiflash® companion System® with RediSep® silica gelcolumn 24 g, 3% MeOH/EtOAc as a eluting solvent) provided off-whitesolid of 6-(2-chloropyridin-3-yl)-1H-benzimidazole (430 mg, 36%). ¹H NMR(DMSO-d6): δ 8.42 (dd, 1H, J=1.7 and 4.7 Hz), 8.24 (s, 1H), 7.91 (dd,1H, J=1.7 and 7.6 Hz), 7.60 (d, 1H, J=8.8 Hz), 7.67 (app d, 1H, J=0.7Hz), 7.53 (dd, 1H, J=J=4.7 and 7.6 Hz), 7.29 (dd, 1H, J=1.7 and 8.8 Hz),3.86 (s, 3H LCMS: rt 3.85 min (A), purity 94%, MS (m/e) 244 (MH⁺).

Example 30 5-(2-Chloropyridin-3-yl)-1H-benzimidazole

5-(2-Chloropyridin-3-yl)-1-methyl-1H-benzimidazole was synthesized inthe similar manner to the preparation of6-(2-Chloropyridin-3-yl)-1-methyl-1H-benzimidazole. ¹H NMR (DMSO-d6): δ8.41 (dd, 1H, J=1.7 and 4.7 Hz), 8.25 (s, 1H), 7.89 (dd, 1H, J=1.7 and7.6 Hz), 7.71 (app d, 1H, J=0.7 Hz), 7.65 (d, 1H, J=8.5 Hz), 7.51 (dd,1H, J=J=4.7 and 7.6 Hz), 7.35 (dd, 1H, J=1.4 and 8.5 Hz), 3.86 (s, 3H).LCMS: rt 3.86 min (A), purity 93%, MS (m/e) 244 (MH⁺).

Example 31 6-(2-Chloropyridin-3-yl)benzoxazole

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,6-(2-chloropyridin-3-yl)benzoxazole was prepared by heating the mixtureof 6-bromo-benzoxazole (1.0 g, 5.1 mmol), 2-chloro-3-pyridine boronicacid pinacol ester (1.5 g, 6.6 mmol), Pd(PPh₃)₄ (400 mg, 0.34 mmol) and2M aq.Na₂CO₃ (8 mL, 16 mmol) in 1,4-dioxane (40 mL). Upon extractivework-up with CH₂Cl₂ and purification (Combiflash® Companion System® withRediSep® silica gel column 24 g, 30-50% EtOAc/hexanes as a elutingsolvent) provided off-white solid f 6-(2-chloropyridin-3-yl)benzoxazole(440 mg, 37%). ¹H NMR (DMSO-d6): δ 8.82 (s, 1H), 8.45 (dd, 1H, J=1.7 and4.7 Hz), 7.95-7.92 (m, 2H), 7.89 (d, 1H, J=8.5 Hz), 7.55 (dd, 1H, J=4.7and 7.6 Hz), 7.49 (d, 1H, J=8.5 Hz). LCMS: rt 5.93 min (B), purity 99%,MS (m/e) 231 (MH⁺).

Example 32 5-(2-Chloropyridin-3-yl)benzoxazole

5-(2-Chloropyridin-3-yl)benzoxazole (310 mg, 25%) was prepared in theidentical manner to the preparation of6-(2-chloropyridin-3-yl)benzoxazole. ¹H NMR (DMSO-d6): δ 8.82 (s, 1H),8.44 (dd, 1H, J=1.7 and 4.7 Hz), 7.95-7.90 (m, 2H), 7.87 (d, 1H, J=8.5Hz), 7.55-7.50 (m, 2H). LCMS: rt 5.96 min (A), purity 94%, MS (m/e) 231(MH⁺).

Example 33 Preparation of 5-bromo-1-ethyl-1H-indazole and5-bromo-2-ethyl-2H-indazole

A stirred mixture of 5-bromo-1H-indazole (2.0 g, 10.1 mmol), iodoethane(2.0, 12.8 mmol), Cs₂CO₃ (4.0 g, 12.27 mmol) was heated in dry DMF at40° C. for 12h under argon. The reaction mixture was cooled, dilutedwith water and EtOAc. Aqueous layer was discarded and the organic layerwas washed with water and aq. NaCl successively. Collected organic layerwas stirred with MgSO₄ for 10 min, filtered and concentrated. The wellseparated (on TLC) regio-isomers were isolated by flash silica gelcolumn chromatography (combiflash 0-30-50% EtOAc/hexanes, 80 g).5-Bromo-1-ethyl-1H-indazole (1.2 g, liquid, 52%). LCMS: rt 7.58 min (A),purity 99%, MS (m/e) 231 (MH⁺). 5-bromo-2-ethyl-2H-indazole (900 mg,liquid, 39%). LCMS: rt 6.98 min (A), purity 97%, MS (m/e) 227 (MH⁺).

Example 34 5-(2-Chloropyridin-3-yl)-2-ethyl-2H-indazole

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,5-(2-chloropyridin-3-yl)-2-ethyl-2H-indazole was prepared by the heatingthe mixture of 5-bromo-2-ethyl-2H-indazole (0.90 g, 3.98 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.1 g, 4.60 mmol),Pd(PPh₃)₄ (300 mg, 0.34 mmol) and 2M aq.Na₂CO₃ (5 mL, 10 mmol) in1,4-dioxane (40 mL). 5-(2-chloropyridin-3-yl)-2-ethyl-2H-indazole (732mg, 70%) was isolated as an off-white solid after the workup andpurification by flash silica gel purification. ¹H NMR (DMSO-d6): δ 8.45(s, 1H), 8.40 (dd, 1H, J=1.7 and 4.7 Hz), 7.89 (dd, 1H, J=1.7 and 7.6Hz), 7.76 (s, 1H), 7.67 (d, 1H, J=9.1 Hz), 7.49 (dd, 1H, J=4.9 and 7.5Hz), 7.29 (d, 1H, J=9.1 Hz), 4.46 (qt, 2H, J=7.3 Hz), 1.40 (t, 3H, J=7.3Hz). LCMS: rt 6.51 min (A), purity 98%, MS (m/e) 258 (MH⁺).

Example 35 5-(2-Chloropyridin-3-yl)-1-ethyl-2H-indazole

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,5-(2-chloropyridin-3-yl)-1-ethyl-1H-indazole was prepared by heating themixture of 5-bromo-1-ethyl-1H-indazole (0.90 g, 3.98 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.1 g, 4.60 mmol),Pd(PPh₃)₄ (300 mg, 0.34 mmol) and 2M aq.Na₂CO₃ (5 mL, 10 mmol) in1,4-dioxane (40 mL). 5-(2-chloropyridin-3-yl)-1-ethyl-1H-indazole (842mg, 82%) was isolated as an off-white solid after the workup and flashsilica gel purification. ¹H NMR (DMSO-d6): δ 8.41 (dd, 1H, J=1.7 and 4.7Hz), 8.11 (s, 1H), 7.92 (dd, 1H, J=1.7 and 7.6 Hz), 7.83 (app t, 1H,J=0.6 Hz), 7.73 (dd, 1H, J=0.6 and 8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.6Hz), 7.46 (dd, 1H, J=1.7 and 8.8 Hz), 4.46 (qt, 2H, J=7.3 Hz), 1.40 (t,3H, J=7.3 Hz). LCMS: rt 5.46 min (B), purity 97%, MS (m/e) 258 (MH⁺).

Example 36 6-(2-Chloropyridin-3-yl)quinoline

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,6-(2-chloropyridin-3-yl)quinoline was prepared by heating the mixture of6-bromoquinoline (1.0 g, 4.8 mmol), 2-chloro-3-pyridine boronic acidpinacol ester (1.5 g, 6.20 mmol), Pd(PPh3)4 (330 mg, 0.28 mmol) and 2Maq.Na₂CO₃ (7 mL, 14 mmol) in 1,4-dioxane (40 mL).6-(2-Chloropyridin-3-yl)quinoline was isolated as a white solid (670 mg)following the extractive work-up with CH₂Cl₂ and purification by flashsilica gel purification. ¹H NMR (DMSO-d6): δ 8.95 (dd, 1H, J=1.2 and 4.4Hz), 8.49 (dd, 1H, J=1.7 and 4.7 Hz), 8.43 (d, 1H, J=8.5 Hz), 8.11-8.09(app m, 2H), 8.01 (dd, 1H, J=1.7 and 7.6 Hz), 7.86 (dd, 1H, J=1.4 and8.8 Hz), 7.61-7.55 (m, 2H). LCMS: rt 4.13 min (A), purity 99%, MS (m/e)241 (MH⁺).

Example 37 6-(2-Chloropyridin-3-yl)isoquinoline

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,6-(2-chloropyridin-3-yl)quinoline was prepared by heating the mixture of6-bromoisoquinoline (1.0 g, 4.8 mmol), 2-chloro-3-pyridine boronic acidpinacol ester (1.5 g, 6.2 mmol), Pd(PPh₃)₄ (330 mg, 0.28 mmol) and 2Maq.Na₂CO₃ (7 mL, 14 mmol) in 1,4-dioxane (40 mL).6-(2-Chloropyridin-3-yl)quinoline was isolated as a white solid (670 mg,57%) upon work-up and purification by flash silica gel columnpurification. ¹H NMR (DMSO-d6): δ 9.37 (s, 1H), 8.55 (dd, 1H, J=1.4 and5.5 Hz), 8.50-8.48 (m, 1H), 8.22 (d, 1H, J=8.5 Hz), 8.07 (s, 1H), 8.01(dt, 1H, J=1.2 and 7.6 Hz), 7.88 (d, 1H, J=5.8 Hz), 7.78 (dd, 1H, J=0.4and 8.5 Hz), 7.58 (dd, 1H, J=4.7 and 7.3 Hz). LCMS: rt 4.01 min (A),purity 97%, MS (m/e) 241 (MH⁺).

Example 38 7-(2-Chloropyridin-3-yl)isoquinoline

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,7-(2-chloropyridin-3-yl)isoquinoline was prepared by heating the mixtureof 7-bromoisoquinoline (1.0 g, 4.8 mmol), 2-chloro-3-pyridine boronicacid pinacol ester (1.5 g, 6.20 mmol), Pd(PPh₃)₄ (330 mg, 0.28 mmol) and2M aq.Na₂CO₃ (7 mL, 14 mmol) in 1,4-dioxane (40 mL).6-(2-Chloropyridin-3-yl)quinoline was isolated as a white solid (820 mg,70%) after the CH₂Cl₂ work-up and silica gel flash column purification.¹H NMR (DMSO-d6): δ 9.37 (s, 1H), 8.55 (d, 1H, J=5.8 Hz), 8.49 (dd, 1H,J=1.7 and 4.7 Hz), 8.23 (s, 1H), 8.07 (d, 1H, J=7.5 Hz), 8.02 (dd, 1H,J=1.7 and 7.6 Hz), 7.91-7.88 (m, 2H), 7.58 (dd, 1H, J=4.7 and 7.6 Hz).LCMS: rt 3.96 min (A), purity 95%, MS (m/e) 241 (MH⁺).

Example 39 6-(2-Chloropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

6-(2-Chloropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine was synthesizedin the similar to 6-(2-chloropyridin-3-yl)benzo[d]thiazole from6-bromo[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 5.0 mmol),2-chloro-3-pyridine boronic acid pinacol ester (1.45 g, 6.0 mmol),Pd(PPh₃)₄ (300 mg, 0.26 mmol) and 2M aq.Na₂CO₃ (8 mL, 16 mmol) in1,4-dioxane (50 mL). Upon workup, the crude residue was dissolved inCH₂Cl₂ (10 mL) and stirred with 50% EtOAc/hexanes (40 mL). The resultingoff-white precipitate was filtered and dried to provide6-(2-chloropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (0.68 g, 58%).¹H NMR (DMSO-d6): δ 9.18 (dd, 1H, J=0.86 and 1.7 Hz), 8.57 (s, 1H), 8.50(dd, 1H, J=1.7 and 4.9 Hz), 8.05 (dd, 1H, J=2.0 and 7.8 Hz), 7.94 (dd,1H, J=0.9 and 9.1 Hz), 7.80 (dd, 1H, J=1.7 and 9.1 Hz), 7.59 (dd, 1H,J=4.7 and 7.6 Hz). LCMS: rt 5.00 min (A), purity 97%, MS (m/e) 231.

Example 40 3-Chloro-2-(4-fluoro-3-methylphenyl)pyridine

3-Chloro-2-(4-fluoro-3-methylphenyl)pyridine was synthesized analogousto the reaction conditions used in the preparation of5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of4-fluoro-3-methylphenyl boronic acid (1.0 g, 6.5 mmol),2-bromo-3-chloropyridine (1.4 g, 7.1 mmol), Pd(PPh₃)₄ (0.45 g, 0.38mmol) and 2M aq. Na₂CO₃ (8 mL, 16 mmol) in 1,4-dioxane (125 mL) underargon atmosphere for 3 h. Upon work-up of the reaction mixture, asdiscussed in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,the crude concentrate was purified by flash silica gel columnchromatography [Combiflash® Companion System® with RediSep® silica gelcolumn 40 g, 10-30% EtOAC/hexanes eluting solvent gradient upon liquidloading on to column] to obtain3-chloro-2-(4-fluoro-3-methylphenyl)pyridine as a white solid (790 mg,54%). ¹H NMR (DMSO-d6): δ 8.60 (dd, 1H, J=1.4 and 4.7 Hz), Hz), 8.02(dd, 1H, J=1.4 and 8.2 Hz), 7.57 (app d, 1H, J=7.3 Hz), 7.54-7.49 (m,1H), 7.42 (dd, 1H, J=4.7 and 8.2 Hz), 7.23 (t, 1H, J=8.8 Hz), 2.28 (s,3H). LCMS: 97%, MS (m/e) 222.

Example 41 3-Chloro-2-(3-methylphenyl)pyridine

3-Chloro-2-(3-methylphenyl)pyridine was synthesized analogous to thereaction conditions used in the preparation of5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of3-methylphenyl boronic acid (1.76 g, 12.9 mmol),2-bromo-3-chloropyridine (2.7 g, 14.2 mmol), Pd(PPh₃)₄ (0.9 g, 0.77mmol) and 2M aq. Na₂CO₃ (16 mL, 32 mmol) in 1,4-dioxane (125 mL) underargon atmosphere for 3 h. Upon work-up of the reaction mixture, asdiscussed in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,the crude concentrate was purified by flash silica gel columnchromatography [Combiflash® Companion System® with RediSep® silica gelcolumn 40 g, 10-30% EtOAC/hexanes eluting solvent gradient upon liquidloading on to column] to obtain 3-chloro-2-(3-methylphenyl)pyridine(1.62 g, 61%) as a clear liquid. ¹H NMR (DMSO-d6): δ 8.60 (dd, 1H, J=1.4and 4.7 Hz), 8.00 (dd, 1H, J=1.4 and 8.2 Hz), 7.44-7.37 (m, 3H), 7.25(app d, 1H, J=8.2 Hz), 2.36 (s, 3H). LCMS: 97%, MS (m/e) 204.

Example 42 1-methyl-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole(Compound 186)

1,4-Dioxane (3 mL) was transferred to a microwave vial (Smith Creator)containing 3-chloro-2-(3-methylphenyl)pyridine (100 mg, 0.49 mmol),1-methyl-1H-benzimidazole boronic acid (95 mg, 0.54 mmol),PdCl₂(dppf)₂.CH₂Cl₂ (35 mg, 0.042 mmol) and 2M aq. Na₂CO₃ (0.6 mL, 1.2mmol). Slow stream of argon was bubbled through the heterogeneous redsolution while stirring the reaction mixture. The vial was capped andheated in a microwave at 150° C. for 50 min. Progress of the reactionwas analyzed by LC/MS. The reaction mixture was passed through a pad ofCelite® and washed the pad with EtOAc (10 mL). The filtrate wasconcentrated and purified by preparative HPLC. Subsequently, productfractions were concentrated, diluted with water, neutralized with aq.NaHCO₃ and extracted with EtOAc. Organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated. The concentrate was dissolved inacetonitrile/water (1:1, 15 mL) and allowed to freeze by externalcooling in dry ice/acetone. Lyophilization of the frozen residueresulted in an off-white solid of1-methyl-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole. ¹H NMR(DMSO-d6): δ 8.64 (dd, 1H, J=1.7 and 4.7 Hz), 8.16 (s, 1H), 7.87 (dd,1H, J=1.7 and 7.6 Hz), 7.51 (d, 1H, J=1.5 Hz), 7.47-7.43 (m, 2H), 7.27(s, 1H), 7.03-6.97 (m, 2H), 6.90 (app d, 1H, J=6.7 Hz), 6.85 (dd, 1H,J=8.5 Hz), 3.76 (s, 3H), 2.19 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −114.29 (s).LCMS: rt 3.16 min (A), purity 97%, MS (m/e) 300 (MH⁺).

Example 43

The following analogs are prepared by the reaction of respective3-chloro-2-arylpyridine and benzimidazole boronic acids by identicalreaction conditions and followed by compound purification procedure asdiscussed with the previous reaction.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 187). ¹H NMR (DMSO-d6): δ 8.63 (dd, 1H, J=1.7 and 4.7 Hz),8.17 (s, 1H), 7.86 (dd, 1H, J=1.7 and 7.6 Hz), 7.53 (s, 1H), 7.48 (d,1H, J=8.2 Hz), 7.46 (dd, 1H, J=4.7 and 7.9 Hz), 7.38 (d, 1H, J=7.9 Hz),6.92-6.83 (m, 3H), 3.77 (s, 3H), 2.12 (s, 3H). ¹⁹F NMR (DMSO-d6): δ−118.91 (s). LCMS: rt 3.51 min (A), purity 97%, MS (m/e) 318 (MH⁺).

1-Methyl-5-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole (Compound 188).¹H NMR (DMSO-d6): δ 8.62 (dd, 1H, J=1.4 and 4.7 Hz), 8.15 (s, 1H), 7.82(dd, 1H, J=1.4 and 7.6 Hz), 7.48-7.40 (m, 3H), 7.28 (s, 1H), 7.02-6.98(m, 3H), 6.88 (d, 1H, J=7.2 Hz), 3.79 (s, 3H), 2.19 (s, 3H). ¹⁹F NMR(DMSO-d6): δ −118.91 (s). LCMS: rt 3.26 min (A), purity 97%, MS (m/e)300 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 189). ¹H NMR (DMSO-d6): δ 8.62 (dd, 1H, J=1.7 and 4.7 Hz),8.16 (s, 1H), 7.82 (dd, 1H, J=1.7 and 7.6 Hz), 7.49-7.37 (m, 4H), 7.00(dd, 1H, J=1.4 and 8.5 Hz), 6.91-6.83 (m, 2H), 3.80 (s, 3H), 2.13 (s,3H). ¹⁹F NMR (DMSO-d6): δ −119.03 (s). LCMS: rt 3.68 min (A), MS (m/e)318 (MH⁺).

Example 44 General Synthetic Method B

1,4-Dioxane (3 mL) was transferred to a microwave vial (Smith Creator)containing 2-chloro-3-arylpyridine (1 eq), respective arylboronicacid/or pinacol ester (1.2-1.3 eq). PdCl₂(PPh₃)₂ (0.1 eq), and 2M aq.Na₂CO₃ (2.2 eq). Slow stream of argon was bubbled through theheterogeneous solution while stirring the reaction mixture. The vial wascapped and heated in a microwave at 150° C. for 50 min. Progress of thereaction was analyzed by LC/MS. At the end of the microwave heating, thereaction mixture was passed through a pad of Celite® and washed the padwith EtOAc (10 mL). The filtrate was concentrated and purified bypreparative HPLC. Subsequently, product fractions were concentrated,diluted with water, neutralized with aq. NaHCO₃ and extracted withEtOAc. Organic layer was dried over anhydrous Na₂SO₄, polish filteredand concentrated. The concentrate was dissolved in acetonitrile/water(1:1, 15 mL) and allowed to freeze by external cooling in dryice/acetone. Lyophilization of the frozen residue provided respectiveanalogs for further characterization.

The following compounds were prepared as described in Example 44 by useof the appropriate arylboronic acid/or pinacol ester:

5-(5-Ethoxy-2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole(Compound 1). ¹H NMR (CD₃OD, 300 MHz): 8.43 (s, 1H), 8.06 (s, 1H), 8.00(m, 1H), 7.77 (bs, 1H), 7.47 (m, 1H), 7.35 (m, 1H), 7.15-7.05 (m, 2H),6.99 (m, 1H), 4.34 (q, 2H), 2.17 (s, 3H), 1.51 (t, 3H); MS (ES) 348.32(M+H);

5-(5-Ethoxy-2-(2-fluorophenyl)pyridin-3-yl)-1H-indazole (Compound 2). ¹HNMR (CD₃OD, 300 MHz): 8.12 (s, 1H), 8.05 (bs, 1H), 7.87 (s, 1H),7.67-7.44 (m, 7H), 6.99 (m, 1H), 4.17 (q, 2H), 1.43 (t, 3H); MS (ES)334.32 (M+H);

5-(5-Ethoxy-2-m-tolylpyridin-3-yl)-1H-indazole (Compound 3). ¹H NMR(CD₃OD, 300 MHz): 8.41 (s, 1H), 8.03 (s, 1H), 8.01 (m, 1H), 7.73 (s,1H), 7.45 (m, 1H), 7.32-7.08 (m, 4H), 7.02 (m, 1H), 4.38 (q, 2H), 2.13(s, 3H), 1.48 (t, 3H); MS (ES) 330.33 (M+H);

5-(5-Ethoxy-2-(4-fluoro-2-isopropoxyphenyl)pyridin-3-yl)-1H-indazole(Compound 4). ¹H NMR (CD₃OD, 300 MHz): 8.13 (s, 1H), 8.08 (s, 1H), 8.01(m, 1H), 7.77 (bs, 1H), 7.49 (m, 1H), 7.36 (m, 1H), 7.11-7.02 (m, 3H),4.34 (q, 2H), 4.23 (t, 1H), 1.48 (t, 3H), 1.41 (d, 6H); MS (ES) 392.36(M+H);

5-(5-Ethoxy-2-(3-fluorophenyl)pyridin-3-yl)-1H-indazole (Compound 5). ¹HNMR (CD₃OD, 300 MHz): 8.29 (m, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 7.46 (m,2H), 7.17 (m, 2H), 6.99-6.94 (m, 3H), 4.22 (q, 2H), 1.46 (t, 3H); MS(ES) 334.34 (M+H);

5-(5-Ethoxy-2-(4-fluorophenyl)pyridin-3-yl)-1H-indazole (Compound 6). ¹HNMR (CD₃OD, 300 MHz): 8.40 (m, 1H), 8.06 (s, 1H), 8.01 (m, 1H), 7.82(bs, 1H), 7.44 (m, 1H), 7.26 (m, 2H), 7.12 (m, 2H), 7.03 (m, 1H), 4.34(q, 2H), 1.51 (t, 3H); MS (ES) 334.33 (M+H);

5-(5-Ethoxy-2-(3,4-difluorophenyl)pyridin-3-yl)-1H-indazole (Compound7). ¹H NMR (CD₃OD, 300 MHz): 8.53 (s, 1H), 8.02 (s, 1H), 7.96 (m, 1H),7.77 (bs, 1H), 7.43 (m, 1H), 7.38 (m, 1H), 7.12 (m, 2H), 7.02 (m, 1H),4.36 (q, 2H), 1.49 (t, 3H); MS (ES) 352.31 (M+H);

5-(2-(4-Fluoro-3-methylphenyl)-5-methoxypyridin-3-yl)-1H-indazole(Compound 8). ¹H NMR (CD₃OD, 300 MHz): 8.28 (bs, 1H), 8.02 (s, 1H),7.64-7.39 (m, 3H), 7.18 (m, 1H), 7.09 (m, 1H), 6.96 (m, 1H), 6.80 (m,1H), 3.95 (s, 3H), 2.11 (s, 3H); MS (ES) 334.46 (M+H);

5-(5-Chloro-2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole(Compound 9). ¹H NMR (CD₃OD, 300 MHz): 8.59 (bs, 1H), 8.02 (m, 1H), 7.94(m, 1H), 7.70 (s, 1H), 7.59 (m, 1H), 7.25 (m, 1H), 7.12 (m, 1H), 7.02(m, 1H), 6.84 (m, 1H), 2.12 (s, 3H); MS (ES) 338.29 (M+H);

5-(5-Fluoro-2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole(Compound 10). ¹H NMR (CD₃OD, 300 MHz): 8.50 (bs, 1H), 8.03 (s, 1H),7.76 (m, 1H), 7.70 (m, 1H), 7.41 (m, 1H), 7.20 (m, 1H), 7.12 (m, 1H),7.01 (m, 1H), 6.84 (m, 1H), 2.12 (s, 3H); MS (ES) 322.31 (M+H);

5-(2-(4-Fluoro-3-methylphenyl)-5-methylpyridin-3-yl)-1H-indazole(Compound 11). ¹H NMR (CD₃OD, 300 MHz): 8.67 (bs, 1H), 8.53 (s, 1H),8.07 (s, 1H), 7.79 (m, 1H), 7.51 (m, 1H), 7.36 (m, 1H), 7.17 (m, 2H),7.02 (m, 1H), 2.65 (s, 3H), 2.20 (s, 3H); MS (ES) 318.36 (M+H);

5-(2-(4-Fluoro-3-methylphenyl)-6-methylpyridin-3-yl)-1H-indazole(Compound 12). ¹H NMR (CD₃OD, 300 MHz): 8.53 (m, 1H), 8.06 (s, 1H), 7.90(m, 1H), 7.75 (bs, 1H), 7.49 (m, 1H), 7.41 (m, 1H), 7.19-7.02 (m, 3H),2.86 (s, 3H), 2.22 (s, 3H); MS (ES) 318.30 (M+H);

5-(2-(4-Cyclopropylphenyl)-6-methylpyridin-3-yl)-1H-indazole (Compound13). ¹H NMR (CD₃OD, 300 MHz): 8.49 (m, 1H), 8.04 (s, 1H), 7.89 (m, 1H),7.74 (s, 1H), 7.47 (m, 1H), 7.28 (m, 2H), 7.10 (m, 3H), 2.86 (s, 3H),1.92 (m, 1H), 1.03 (m, 2H), 0.69 (m, 2H); MS (ES) 326.28 (M+H);

5-(2-(3-Isopropylphenyl)-6-methylpyridin-3-yl)-1H-indazole (Compound14). ¹H NMR (CD₃OD, 300 MHz): 8.55 (m, 1H), 8.03 (s, 1H), 7.92 (m, 1H),7.72 (s, 1H), 7.47-7.35 (m, 4H), 7.13 (m, 2H), 2.87 (s, 3H), 2.75 (t,1H), 0.98 (3H), 0.96 (3H); MS (ES) 328.31 (M+H);

6-(3-Cyclopropylphenyl)-5-(1H-indazol-5-yl)pyridin-3-amine (Compound15). ¹H NMR (CD₃OD, 300 MHz): 8.01 (m, 2H), 7.60 (s, 1H), 7.36 (m, 1H),7.25 (m, 1H), 7.06-6.93 (m, 4H), 6.76 (s, 1H), 1.69 (m, 1H), 0.73 (m,2H), 0.27 (m, 2H); MS (ES) 327.27 (M+H);

5-(1H-Indazol-5-yl)-6-(3-isopropylphenyl)pyridin-3-amine (Compound 16).¹H NMR (CD₃OD, 300 MHz): 8.03 (m, 1H), 8.00 (s, 1H), 7.80 (m, 1H), 7.71(m, 1H), 7.47 (m, 1H), 7.32-7.10 (m, 4H), 7.00 (s, 1H), 2.65 (t, 1H),0.94 (d, 6H); MS (ES) 329.29 (M+H);

6-(4-Fluoro-3-methylphenyl)-5-(1H-indazol-5-yl)pyridin-3-amine (Compound17). ¹H NMR (CD₃OD, 300 MHz): 8.82 (m, 1H), 8.41 (s, 1H), 8.20 (m, 1H),8.01 (m, 2H), 7.62 (m, 1H), 7.32 (m, 1H), 7.05-6.82 (m, 2H), 2.12 (s,3H); MS (ES) 319.12 (M+H);

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-amine(Compound 18). ¹H NMR (CD₃OD, 300 MHz): 9.21 (s, 1H), 8.05 (s, 1H), 7.92(m, 2H), 7.62 (m, 1H), 7.29 (m, 1H), 7.26-7.17 (m, 1H), 6.88 (m, 1H),6.77 (m, 1H), 2.12 (s, 3H); MS (ES) 336.25 (M+H);

5-(Benzo[d]thiazol-6-yl)-6-(3-cyclopropylphenyl)pyridin-3-amine(Compound 19). ¹H NMR (CD₃OD, 300 MHz): 9.21 (s, 1H), 8.05 (m, 1H), 7.91(m, 1H), 7.84 (s, 1H), 7.29 (m, 1H), 7.25 (m, 1H), 7.08-6.93 (m, 3H),6.75 (s, 1H), 1.70 (m, 1H), 0.73 (m, 2H), 0.27 (m, 2H); MS (ES) 344.28(M+H);

5-(Benzo[d]thiazol-6-yl)-6-m-tolylpyridin-3-amine (Compound 20). ¹H NMR(CD₃OD, 300 MHz): 9.21 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 8.84 (m,1H), 7.29-7.01 (m, 5H), 6.90 (m, 1H), 2.19 (s, 3H); MS (ES) 318.28(M+H);

6-(4-Fluoro-3-methylphenyl)-5-(1H-indazol-5-yl)pyridin-2-amine (Compound21). ¹H NMR (CD₃OD, 300 MHz): 8.10 (m, 1H), 8.01 (s, 1H), 7.66 (s, 1H),7.42 (m, 1H), 7.31 (m, 1H), 7.13-7.00 (m, 3H), 6.96 (m, 1H), 2.19 (s,3H); MS (ES) 319.25 (M+H);

6-(3-Cyclopropylphenyl)-5-(1H-indazol-5-yl)pyridin-2-amine (Compound22). ¹H NMR (CD₃OD, 300 MHz): 8.09 (m, 1H), 8.00 (s, 1H), 7.63 (s, 1H),7.44 (m, 1H), 7.27-7.11 (m, 5H), 6.95 (s, 1H), 1.80 (m, 1H), 0.84 (m,2H), 0.37 (m, 2H); MS (ES) 327.28 (M+H);

5-(1H-Indazol-5-yl)-6-m-tolylpyridin-2-amine (Compound 23). ¹H NMR(CD₃OD, 300 MHz): 8.10 (m, 1H), 8.07 (s, 1H), 7.65 (s, 1H), 7.42 (m,1H), 7.24 (m, 3H), 7.08 (m, 3H), 2.27 (s, 3H); MS (ES) 301.26 (M+H);

N-(6-(4-Fluoro-3-methylphenyl)-5-(1H-indazol-5-yl)pyridin-3-yl)acetamide(Compound 24). ¹H NMR (CD₃OD, 300 MHz): 9.21 (s, 1H), 8.38 (m, 1H), 8.07(s, 1H), 7.76 (s, 1H), 7.50 (m, 1H), 7.32 (m, 1H), 7.11 (m, 2H), 6.98(m, 1H), 2.25 (s, 3H), 2.18 (s, 3H); MS (ES) 361.21 (M+H);

N-(6-(3-Cyclopropylphenyl)-5-(1H-indazol-5-yl)pyridin-3-yl)acetamide(Compound 25). ¹H NMR (CD₃OD, 300 MHz): 9.24 (s, 1H), 8.38 (m, 1H), 8.06(s, 1H), 7.74 (m, 1H), 7.49 (m, 1H), 7.26-7.11 (m, 3H), 6.95 (s, 1H),2.25 (s, 3H), 1.82 (m, 1H), 0.85 (m, 2H), 0.37 (m, 2H); MS (ES) 369.27(M+H);

N-(5-(1H-Indazol-5-yl)-6-m-tolylpyridin-3-yl)acetamide (Compound 26). ¹HNMR (CD₃OD, 300 MHz): 9.25 (s, 1H), 8.40 (m, 1H), 8.05 (s, 1H), 7.74 (s,1H), 7.48 (m, 1H), 7.24-7.06 (m, 4H), 2.26 (s, 3H), 2.25 (s, 3H); MS(ES) 343.27 (M+H);

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-2-amine(Compound 27). ¹H NMR (CD₃OD, 300 MHz): 9.26 (s, 1H), 8.11 (m, 1H), 8.08(s, 1H), 7.95 (m, 1H), 7.35 (m, 2H), 7.11 (m, 2H), 7.01 (m, 1H), 2.20(s, 3H); MS (ES) 336.26 (M+H);

5-(Benzo[d]thiazol-6-yl)-6-(3-cyclopropylphenyl)pyridin-2-amine(Compound 28). ¹H NMR (CD₃OD, 300 MHz): 9.26 (s, 1H), 8.12 (m, 1H), 8.09(m, 1H), 7.92 (s, 1H), 7.30-7.10 (m, 4H), 6.97 (s, 1H), 1.81 (m, 1H),0.85 (m, 2H), 0.38 (m, 2H); MS (ES) 344.33 (M+H);

5-(Benzo[d]thiazol-6-yl)-6-m-tolylpyridin-2-amine (Compound 29). ¹H NMR(CD₃OD, 300 MHz): 9.25 (s, 1H), 8.12 (m, 1H), 7.95 (m, 2H), 7.31-7.10(m, 3H), 7.08 (m, 2H), 2.28 (s, 3H); MS (ES) 318.31 (M+H);

N-(6-(4-Fluoro-3-methylphenyl)-5-(1H-indazol-5-yl)pyridin-3-yl)methanesulfonamide(Compound 30). ¹H NMR (CD₃OD, 300 MHz): 8.57 (s, 1H), 8.06 (s, 1H), 8.02(m, 1H), 7.74 (m, 1H), 7.48 (m, 2H), 7.29 (m, 1H), 7.11 (m, 1H), 6.93(m, 1H), 3.19 (s, 3H), 2.16 (s, 3H); MS (ES) 397.21 (M+H);

N-(6-(3-Cyclopropylphenyl)-5-(1H-indazol-5-yl)pyridin-3-yl)methanesulfonamide (Compound 31). ¹H NMR (CD₃OD, 300 MHz): 8.58 (s, 1H),8.08 (m, 2H), 7.72 (s, 1H), 7.47 (m, 1H), 7.21-7.10 (m, 4H), 6.92 (s,1H), 3.20 (s, 3H), 1.77 (m, 1H), 0.81 (m, 2H), 0.34 (m, 2H); MS (ES)405.26 (M+H);

N-(5-(1H-Indazol-5-yl)-6-m-tolylpyridin-3-yl) methanesulfonamide(Compound 32). ¹H NMR (CD₃OD, 300 MHz): 8.61 (s, 1H), 8.15 (m, 1H), 8.05(s, 1H), 7.74 (s, 1H), 7.48 (m, 1H), 7.44 (m, 1H), 7.23-7.05 (m, 4H),3.23 (s, 3H), 2.26 (s, 3H); MS (ES) 379.25 (M+H).

6-(2-m-Tolylpyridin-3-yl)isoquinoline (Compound 33). ¹H NMR (DMSO-d6): δ9.77 (s, 1H), 9.03-8.73 (m, 1H), 8.65 (d, J=6.4 Hz, 1H), 8.34 (dd,J=18.1, 8.1 Hz, 3H), 8.22-8.03 (m, 1H), 7.67 (ddd, J=7.8, 5.0, 1.2 Hz,1H), 7.58 (dd, J=8.6, 1.4 Hz, 1H), 7.27 (s, 1H), 7.07 (dt, J=15.0, 7.5Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 2.17 (s, 3H). MS (m/e): 297 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)isoquinoline (Compound 34).¹H NMR (DMSO-d6): δ 9.79 (s, 1H), 8.83-8.72 (m, 1H), 8.66 (d, J=6.4 Hz,1H), 8.45-8.22 (m, 3H), 8.09 (dd, J=7.8, 1.5 Hz, 1H), 7.71-7.51 (m, 2H),7.38 (d, J=7.4 Hz, 1H), 6.97-6.88 (m, 2H), 2.09 (s, 3H). MS (m/e): 315(MH⁺).

6-(2-(3-Fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound 59).¹H NMR (DMSO-d6): δ 9.05-8.98 (m, 1H), 8.79 (dd, J=4.8, 1.6 Hz, 1H),8.37-8.30 (m, 1H), 8.20 (d, J=2.1 Hz, 1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H),7.85 (d, J=9.3 Hz, 1H), 7.67-7.47 (m, 2H), 7.42-7.23 (m, 2H), 7.23-7.07(m, 2H). MS (m/e): 290 (MH⁺).

N-(3-(3-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2-yl)phenyl)methylsulphonamide(Compound 58). ¹H NMR (DMSO-d6): δ 9.63 (s, 1H), 9.02 (s, 1H), 8.79 (dd,J=4.8, 1.2 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.01(dd, J=7.8, 1.3 Hz, 1H), 7.85 (d, J=9.4 Hz, 1H), 7.60 (dd, J=7.8, 4.8Hz, 1H), 7.46 (dd, J=9.3, 1.2 Hz, 1H), 7.33 (d, J=5.9 Hz, 2H), 7.12 (dd,J=10.0, 6.8 Hz, 2H), 2.71 (s, 3H). MS (m/e): 366 (MH⁺).

3-(3-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2-yl)benzenamine (Compound 56).¹H NMR (DMSO-d6): δ 9.04 (d, J=3.5 Hz, 1H), 8.80 (dd, J=4.8, 0.7 Hz,1H), 8.34 (d, J=2.1 Hz, 1H), 8.24-8.16 (m, 1H), 8.03 (dd, J=7.8, 0.9 Hz,1H), 7.85 (d, J=9.3 Hz, 1H), 7.62 (dd, J=7.5, 5.1 Hz, 1H), 7.47 (dd,J=9.3, 0.9 Hz, 1H), 7.39-7.09 (m, 4H). MS (m/e): 287 (MH⁺).

6-(2-(3,5-Difluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound55). ¹H NMR (DMSO-d6): δ 9.04-8.96 (m, 1H), 8.78 (dd, J=4.8, 1.6 Hz,1H), 8.35 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.1 Hz, 1H), 8.03 (dd, J=7.8,1.6 Hz, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.60 (ddd, J=11.0, 8.6, 3.2 Hz,2H), 7.27-6.96 (m, 3H). MS (m/e): 308 (MH⁺).

6-(2-(4-Trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 57). ¹H NMR (DMSO-d6): δ 9.04 (s, 1H), 8.82 (dd, J=4.7, 1.1Hz, 1H), 8.34 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.04 (dd, J=7.8, 1.1 Hz,1H), 7.85 (d, J=9.3 Hz, 1H), 7.72-7.54 (m, 5H), 7.50 (d, J=9.3 Hz, 1H).MS (m/e): 340 (MH⁺).

6-(2-(4-Methoxyphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound 54).¹H NMR (DMSO-d6): δ 9.03 (s, 1H), 8.79 (dd, J=4.9, 1.5 Hz, 1H), 8.35 (d,J=1.5 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.08 (dd, J=7.8, 1.5 Hz, 1H),7.85 (d, J=9.3 Hz, 1H), 7.64 (dd, J=7.8, 5.0 Hz, 1H), 7.48 (dd, J=9.3,1.5 Hz, 1H), 7.40-7.30 (m, 2H), 6.86 (d, J=8.8 Hz, 2H), 3.72 (s, 3H). MS(m/e): 302 (MH⁺).

6-(2-(3-Methoxyphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound 52).¹H NMR (DMSO-d6): δ 8.98 (s, 1H), 8.78 (d, J=4.8 Hz, 1H), 8.30 (s, 1H),8.17 (d, J=1.0 Hz, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.81 (d, J=9.3 Hz, 1H),7.63 (dd, J=7.8, 4.9 Hz, 1H), 7.50 (d, J=9.4 Hz, 1H), 7.16 (t, J=7.9 Hz,1H), 7.02 (s, 1H), 6.94-6.77 (m, 3H), 3.64 (s, 3H). MS (m/e): 302 (MH⁺).

3-(3-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2-yl)benzonitrile (Compound51). ¹H NMR (DMSO-d6): δ 9.01 (s, 1H), 8.81 (dd, J=4.8, 1.6 Hz, 1H),8.33 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H), 8.03 (dd, J=7.8, 1.6 Hz,1H), 7.91 (d, J=1.6 Hz, 1H), 7.88-7.74 (m, 2H), 7.66-7.60 (m, 2H),7.56-7.37 (m, 2H). MS (m/e): 297

6-(2-(4-Fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound 53).¹H NMR (DMSO-d6): δ 9.01 (s, 1H), 8.78 (dd, J=4.8, 1.5 Hz, 1H),8.37-8.30 (m, 1H), 8.20 (d, J=1.2 Hz, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.84(d, J=9.4 Hz, 1H), 7.60 (dd, J=7.8, 4.9 Hz, 1H), 7.54-7.38 (m, 3H), 7.11(t, J=8.7 Hz, 2H). MS (m/e): 290 (MH⁺).

5-(2-(2-Fluorophenyl)pyridin-3-yl)-1H-indazole (Compound 61). ¹H NMR(DMSO-d6): δ 13.05 (s, 1H), 8.66 (dd, 1H, J=1.4 and 4.7 Hz), 7.98 (s,1H), 7.90 (dd, 1H, J=1.4 and 7.6 Hz), 7.56 (app s, 1H), 7.51 (dd, 1H,J=4.7 and 7.9 Hz), 7.44-7.32 (m, 2H), 7.31-7.27 (m, 1H), 7.16 (dt, 1H,J=0.8 and 7.6 Hz), 7.01 (dd, 1H, J=1.4 and 8.5 Hz), 6.96 (app t, 1H,J=8.5 Hz). ¹⁹F NMR (DMSO-d6): δ −118.91. LCMS: rt 4.65 min (A), purity97%, MS (m/e) 290 (MH⁺).

5-(2-(3,4-Difluorophenyl)pyridin-3-yl)-1H-indazole (Compound 62). LCMS:rt 5.20 min (A), purity 98%, MS (m/e) 308 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole (Compound 63).¹H NMR (DMSO-d6): δ 13.05 (s, 1H), 8.62 (dd, 1H, J=0.5 and 4.7 Hz), 8.04(s, 1H), 7.83 (d, 1H, J=7.6 Hz), 7.66 (s, 1H), 7.45-7.34 (app m, 3H),7.02 (d, 1H, J=8.5 Hz), 6.96-6.85 (m, 2H), 2.11 (s, 3H). ¹⁹F NMR(DMSO-d6): δ −118.91. LCMS: rt 4.87 min (A), purity 99% MS (m/e) 304(MH⁺).

5-(3-(1H-Indazol-5-yl)pyridin-2-yl)-1H-indazole (Compound 64). ¹H NMR(DMSO-d6): δ 13.04 (s, 1H), 12.99 (s, 1H), 8.66 (dd, 1H, J=1.2 and 4.7Hz), 8.01 (s, 1H), 7.95 (s, 1H), 7.85 (dd, 1H, J=1.2 and 7.9 Hz), 7.74(s, 1H), 7.69 (s, 1H), 7.44 (dd, 1H, J=4.7 and 7.9 Hz), 7.34 (d, 1H,J=8.8 Hz), 7.30 (d, 1H, J=8.8 Hz), 7.22 (dd, 1H, J=1.4 and 8.8 Hz), 7.01(d, 1H, J=8.8 Hz). LCMS: rt 3.87 min (A), purity 97%, MS (m/e) 312(MH⁺).

5-[2-(3-Fluorophenyl)pyridin-3-yl]-1H-indazole (Compound 65). ¹H NMR(DMSO-d6): δ 13.10 (s, 1H), 8.68 (dd, 1H, J=1.4 and 4.4 Hz), 8.05 (s,1H), 7.92 (dd, 1H, J=1.4 and 7.9 Hz), 7.67 (s, 1H), 7.53 (dd, 1H, J=4.9and 7.6 Hz), 7.43 (d, 1H, J=8.5 Hz), 7.26-7.13 (m, 1H), 7.14-7.02 (m,4H). ¹⁹F NMR (DMSO-d6): δ −113.58 (qt, J=8.6 Hz) (s). LCMS: rt 4.73 min(A), purity 99%, MS (m/e) 290 (MH⁺).

5-[2-(4-Fluorophenyl)pyridin-3-yl]-1H-indazole (Compound 66). ¹H NMR(DMSO-d6): δ 13.12 (s, 1H), 8.65 (dd, 1H, J=1.7 and 4.7 Hz), 8.04 (s,1H), 7.89 (dd, 1H, J=1.7 and 7.9 Hz), 7.66 (s, 1H), 7.48 (dd, 1H, J=4.7and 7.6 Hz), 7.41 (d, 1H, J=8.2 Hz), 7.34-7.29 (m, 2H), 7.07-6.99 (m,3H). ¹⁹F NMR (DMSO-d6): δ −114.12 (qt, J=8.6 Hz) (s). LCMS: rt 4.53 min(A), purity 97%, MS (m/e) 290 (MH⁺).

5-[2-(3,5-Difluorophenyl)pyridin-3-yl]-1H-indazole (Compound 67). ¹H NMR(DMSO-d6): δ 13.12 (s, 1H), 8.65 (dd, 1H, J=1.7 and 4.7 Hz), 8.07 (s,1H), 7.89 (dd, 1H, J=1.7 and 7.6 Hz), 7.68 (s, 1H), 7.54 (dd, 1H, J=4.7and 7.6 Hz), 7.46 (d, 1H, J=8.2 Hz), 7.14-7.04 (m, 2H), 6.94-6.90 (m,2H). ¹⁹F NMR (DMSO-d6): δ −110.30 (t, J=7.8 Hz)). LCMS: rt 5.62 min (A),purity 97%, MS (m/e) 308 (MH⁺).

5-(2-m-Tolylpyridin-3-yl)-1H-indazole (Compound 68). ¹H NMR (DMSO-d6): δ13.12 (s, 1H), 8.70 (dd, 1H, J=1.7 and 4.7 Hz), 8.06-8.03 (m, 2H), 7.67(s, 1H), 7.60 (dd, 1H, J=4.7 and 7.6 Hz), 7.42 (d, 1H, J=7.8 Hz), 7.28(s, 1H), 7.08-6.94 (m, 4H), 2.19 (s, 3H). LCMS: rt 4.62 min (A), purity97%, MS (m/e) 286 (MH⁺).

5-(2-p-Tolylpyridin-3-yl)-1H-indazole (Compound 69). ¹H NMR (DMSO-d6): δ13.38 (s, 1H), 8.64 (dd, 1H, J=1.7 and 4.9 Hz), 8.03 (s, 1H), 7.86 (dd,1H, J=1.4 and 7.6 Hz), 7.65 (s, 1H), 7.46 (dd, 1H, J=4.9 and 7.6 Hz),7.39 (d, 1H, J=8.8 Hz), 7.18 (d, 2H, J=8.2 Hz), 7.03-6.99 (m, 3H), 2.21(s, 3H). LCMS: rt 4.65 min (A), purity 97%, MS (m/e) 286 (MH⁺).

5-[2-(2,4-Difluorophenyl)pyridin-3-yl]-1H-indazole (Compound 70). ¹H NMR(DMSO-d6): δ 13.28 (s, 1H), 8.67 (dd, 1H, J=1.4 and 4.8 Hz), 8.01 (s,1H), 7.94 (dd, 1H, J=1.4 and 7.9 Hz), 7.58-7.44 (m, 3H), 7.40 (d, 1H,J=8.5 Hz), 7.10-7.00 (app m, 3H). ¹⁹F NMR (DMSO-d6): δ −110.06 (q, J=8.6Hz), −110.56 (qt, J=8.6 Hz) LCMS: rt 5.07 min (A), purity 97%, MS (m/e)308 (MH⁺).

5-[2-(3,5-Dimethylphenyl)pyridin-3-yl]-1H-indazole (Compound 71). ¹H NMR(DMSO-d6): δ 13.38 (s, 1H), 8.73 (dd, 1H, J=1.4 and 4.9 Hz), 8.15 (dd,1H, J=1.7 and 7.9 Hz), 8.06 (s, 1H), 7.69 (app t, 2H, J=6.7 Hz), 7.86(dd, 1H, J=1.4 and 7.6 Hz), 7.43 (d, 1H, J=8.5 Hz), 7.03 (dd, 1H, J=1.7and 8.8 Hz), 6.94 (s, 3H), 2.09 (s, 6H). LCMS: rt 4.93 min (A), purity97%, MS (m/e) 300 (MH⁺).

5-(2-(3-Fluoro-4-methylphenyl)pyridin-3-yl)-1H-indazole (Compound 72).¹H NMR (DMSO-d6): δ 8.72 (dd, 1H, J=1.4 and 4.9 Hz), 8.07 (d, 1H, J=0.8Hz), 8.06 (dd, 1H, J=1.4 and 7.9 Hz), 7.69 (app d, 1H, J=0.8 Hz), 7.62(dd, 1H, J=4.9 and 7.9 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.15-7.09 (m, 2H),7.04 (dd, 1H, J=1.7 and 8.5 Hz), 6.97 (dd, 1H, J=1.7 and 7.9 Hz), 2.19(s, 3H). LCMS: rt 4.98 min (A), purity 97%, MS (m/e) 304 (MH⁺).

5-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)-1H-indazole (Compound 73).¹H NMR (DMSO-d6): δ 13.28 (s, 1H), 8.72 (dd, 1H, J=1.4 and 4.7 Hz), 8.05(dd, 1H, J=1.4 and 7.9 Hz), 8.01 (s, 1H), 7.64 (dd, 1H, J=4.9 and 7.9Hz), 7.60 (s, 1H), 7.39 (d, 1H, J=8.8 Hz), 7.32 (d, 1H, J=1.8 and 8.8Hz), 7.17-7.14 (m, 1H), 7.07 (dd, 1H, J=1.7 and 8.5 Hz), 6.86 (app t,1H, J=7.6 Hz), 2.25 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −119.68. LCMS: rt 4.95min (A), purity 97%, MS (m/e) 304 (MH⁺).

5-(2-(2-Fluoro-4-methylphenyl)pyridin-3-yl)-1H-indazole (Compound 74).¹H NMR (DMSO-d6): δ 13.43 (s, 1H), 8.73 (dd, 1H, J=1.4 and 4.9 Hz), 8.11(dd, 1H, J=1.4 and 7.9 Hz), 8.02 (s, 1H), 7.69 (dd, 1H, J=4.9 and 7.9Hz), 7.61 (s, 1H), 7.40 (d, 1H, J=8.8 Hz), 7.33 (t, 1H, J=7.6 Hz), 7.06(dd, 1H, J=1.4 and 8.5 Hz), 7.01 (d, 1H, J=7.6 Hz), 6.86 (d, 1H, J=11Hz), 2.25 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −115.46 (dd, J=7.6 and 11 Hz).LCMS: rt 4.88 min (A), purity 97%, MS (m/e) 304 (MH⁺).

5-(2-(3-Aminophenyl)pyridin-3-yl)-1H-indazole (Compound 75). LCMS: rt3.43 min (A), purity 97%, MS (m/e) 287 (MH⁺).

5-(2-(3-Methylsulfphonylaminophenyl)pyridin-3-yl)-1H-indazole (Compound76). ¹H NMR (DMSO-d6): δ 9.67 (s, 1H), 8.72 (dd, 1H, J=1.4 and 4.9 Hz),8.06 (d, 1H, J=7.9 Hz), 8.05 (s, 1H), 7.67 (s, 1H), 7.64 (dd, 1H, J=4.9and 7.6 Hz), 7.42 (d, 1H, J=8.5 Hz), 7.21 (d, 1H, J=7.9 Hz), 7.18 (s,1H), 7.10-7.02 (m, 3H), 2.56 (s, 3H). LCMS: rt 3.97 min (A), purity 97%,MS (m/e) 365 (MH⁺).

5-(2-(3,4-Difluorophenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 77). ¹H NMR (DMSO-d6): δ 13.65 (s, 1H), 8.70 (d, 1H, J=4.7Hz), 8.22 (s, 1H), 8.14 (s, 2H), 7.96 (d, 1H, J=7.6 Hz), 7.53 (dd, 1H,J=4.7 and 7.9 Hz), 7.39 (app t, 1H, J=9.7 Hz), 7.29 (qt, 1H, J=8.6 Hz),7.03-6.98 (m, 1H). ¹⁹F NMR (DMSO-d6): δ −138.69-138.84 (app m),−139.47-139.55 (app m). LCMS: rt 4.26 min (B), purity 97%, MS (m/e) 309(MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 78). ¹H NMR (DMSO-d6): δ 13.65 (s, 1H), 8.67 (d, 1H, J=4.7Hz), 8.18 (d, 1H, J=2.0 Hz), 8.12 (d, 2H, J=2.0 Hz), 7.92 (d, 1H, J=7.6Hz), 7.49 (dd, 1H, J=4.7 and 7.6 Hz), 7.35 (d, 1H, J=7.6 Hz), 6.93 (d,2H, J=7.9 Hz), 2.12 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −118.53 (s). LCMS: rt3.81 min (B), purity 97%, MS (m/e) 305 (MH⁺).

5-(2-m-Tolylpyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (Compound 79). ¹HNMR (DMSO-d6): δ 13.65 (s, 1H), 8.67 (d, 1H, J=4.7 Hz), 8.16 (s, 1H),8.11 (s, 2H), 7.92 (d, 1H, J=6.7 Hz), 7.49 (dd, 1H, J=4.7 and 7.6 Hz),7.23 (s, 1H), 7.05 (s, 1H), 7.04 (s, 1H), 6.91 (app d, 1H, J=6.7 Hz),2.19 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −118.91 (s). LCMS: rt 3.29 min (B),purity 97%, MS (m/e) 287 (MH⁺).

5-(2-(4-Fluorophenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (Compound80). ¹H NMR (DMSO-d6): δ 13.65 (s, 1H), 8.65 (dd, 1H, J=1.4 and 4.7 Hz),8.17 (s, 1H), 8.12 (s, 2H), 7.93 (dd, 1H, J=1.4 and 7.6 Hz), 7.51 (dd,1H, J=4.7 and 7.9 Hz), 7.30 (app d, 1H, J=4.7 and 8.8 Hz), 7.07 (app t,2H, J=8.8 Hz). ¹⁹F NMR (DMSO-d6): δ −114.06 (s). LCMS: rt 3.42 min (B),purity 97%, MS (m/e) 291 (MH⁺).

5-(2-(3-Fluoro-4-methylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 81). LCMS: rt 4.17 min (B), purity 97%, MS (m/e) 305 (MH⁺).

5-(2-(2-Fluoro-4-methylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 82). LCMS: rt 4.07 min (B), purity 97%, MS (m/e) 305 (MH⁺).

2-(2-Fluorophenyl)-3-(4-flurophenyl)pyridine (Compound 83). LCMS: rt5.89 min (B), purity 97%, MS (m/e) 268 (MH⁺).

2-(3,4-Difluorophenyl)-3-(4-flurophenyl)pyridine (Compound 84). LCMS: rt6.52 min (B), purity 97%, MS (m/e) 286 (MH⁺).

2-(4-Fluoro-3-methylphenyl)-3-(4-flurophenyl)pyridine (Compound 85). ¹HNMR (DMSO-d6): δ 8.77 (dd, 1H, J=1.4 and 5.3 Hz), 8.19 (d, 1H, J=7.6Hz), 7.77 (dd, 1H, J=5.3 and 7.6 Hz), 7.36 (d, 1H, J=7.2 Hz), 7.26-7.15(m, 4H), 7.08 (app d, 2H, J=8.5 Hz), 2.16 (s, 3H). ¹⁹F NMR (DMSO-d6): δ−113.94 (s), −116.31 (s). LCMS: 6.10 min (B), purity 97%, MS (m/e) 282(MH⁺).

2-(3-Fluorophenyl)-3-(4-flurophenyl)pyridine (Compound 86). LCMS: rt6.11 min (B), purity 97%, MS (m/e) 268 (MH⁺).

2,3-Bis-(4-fluorophenyl)pyridine (Compound 87). LCMS: rt 5.70 min (B),purity 97%, MS (m/e) 268 (MH⁺).

3-(4-Fluorophenyl)-2-m-tolylpyridine (Compound 88). LCMS: rt 5.70 min(B), purity 97%, MS (m/e) 264 (MH⁺).

(5-(3-(1H-Indazol-5-yl)pyridin-2-yl)-2-fluorophenyl)methanol (Compound89). ¹H NMR (DMSO-d6): δ 8.64 (dd, 1H, J=1.4 and 4.7 Hz), 8.04 (s, 1H),7.84 (dd, 1H, J=1.4 and 7.6 Hz), 7.67-7.64 (app m, 2H), 7.44 (d, 1H,J=4.7 and 7.6 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.01 (dd, 1H, J=1.4 and 8.8Hz), 6.98-6.93 (m, 1H), 6.87 (t, 1H, J=8.8 Hz), 5.20 (t, 1H, J=5.5 Hz),4.45 (d, 2H, J=5.5 Hz). ¹⁹F NMR (DMSO-d6): δ −118.91 (s). LCMS: rt 2.87min (B), purity 97%, MS (m/e) 320 (MH⁺).

4-(3-(1H-Indazol-5-yl)pyridin-2-yl)-2-methylbenzenamine (Compound 90).LCMS: rt 2.22 min (B), purity 97%, MS (m/e) 301 (MH⁺).

[3-(3-(1H-Indazol-5-yl)pyridin-2-yl)phenyl]methanol (Compound 91). ¹HNMR (DMSO-d6): δ 13.1 (s, 1H), 8.63 (dd, 1H, J=1.4 and 4.7 Hz), 8.02 (s,1H), 7.83 (dd, 1H, J=1.7 and 7.9 Hz), 7.65 (s, 1H), 7.46-7.37 (m, 3H),7.16 (d, 1H, J=7.6 Hz), 7.04 (d, 1H, J=7.9 Hz), 7.01 (dd, 1H, J=1.4 and7.9 Hz), 6.95 (d, 1H, J=7.6 Hz), 5.13 (bs, 1H), 4.38 (s, 2H). LCMS: rt2.54 min (B), purity 97%, MS (m/e) 302 (MH⁺).

4-(3-(1H-Indazol-5-yl)pyridin-2-yl)-N,N,2-trimethylbenzenamine (Compound92). ¹H NMR (DMSO-d6): δ 13.01 (s, 1H), 8.58 (dd, 1H, J=0.4 and 4.4 Hz),8.04 (s, 1H), 7.77 (d, 1H, J=7.6 Hz), 7.67 (s, 1H), 7.41 (app d, 1H,J=7.6 Hz), 7.37 (dd, 1H, J=4.8 and 7.6 Hz), 7.25 (s, 1H). 7.03 (d, 1H,J=8.5 Hz), 6.90 (app d 1H, J=7.6 Hz), 6.72 (d, 1H, J=8.5 Hz), 2.55 (s,6H), 2.11 (s, 3H). LCMS: rt 2.39 min (B), purity 97%, MS (m/e) 329(MH⁺).

5-(2-(4-Fluoro-3-(trifluoromethyl)phenyl)pyridin-3-yl)-1H-indazole(Compound 93). ¹H NMR (DMSO-d6): δ 13.1 (s, 1H), 8.70 (dd, 1H, J=1.4 and4.7 Hz), 8.06 (s, 1H), 7.94 (dd, 1H, J=1.7 and 7.9 Hz), 7.70 (app s,2H), 7.56 (d, 1H, J=7.9 Hz), 7.54 (d, 1H, J=7.9 Hz), 7.45 (d, 1H, j=8.8Hz), 7.33 (app t, 1H, J=8.8 Hz), 7.05 (dd, 1H, J 1.5 and 8.5 Hz). ¹⁹FNMR (DMSO-d6): δ −117.12 (app m), −60.34 (d, 1H, J=15 Hz). LCMS: rt 6.22min (A), purity 97%, MS (m/e) 358 (MH⁺).

2-Fluoro-5-(3-(1H-indazol-5-yl)pyridin-2-yl)benzamide (Compound 94).LCMS: rt 3.07 min (A), purity 97%, MS (m/e) 333 (MH⁺).

2-Fluoro-5-(3-(1H-indazol-5-yl)pyridin-2-yl)-N,N-dimethylbenzamide(Compound 95). LCMS: rt 3.42 min (A), purity 97%, MS (m/e) 361 (MH⁺).

5-(3-(1H-Indazol-5-yl)pyridin-2-yl)-2-fluoro-N-propylb enz amide(Compound 96). LCMS: rt 4.06 min (A), purity 97%, MS (m/e) 375 (MH⁺).

6-(2-(2-Fluorophenyl)pyridin-3-yl)-1H-indazole (Compound 97). LCMS: rt4.50 min (A), purity 97%, MS (m/e) 290 (MH⁺).

6-(2-(3,4-Difluorophenyl)pyridin-3-yl)-1H-indazole (Compound 98). LCMS:rt 5.53 min (A), purity 97%, MS (m/e) 308 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole (Compound 99).¹H NMR (DMSO-d6): δ 13.02 (s, 1H), 8.65 (d, 1H, J=4.7 Hz), 8.03 (d, 1H,J=0.5 Hz), 7.87 (d, 1H, J=7.6 Hz), 7.64 (d, 1H, J=8.2 Hz), 7.46 (dd, 1H,J=4.7 and 7.6 Hz), 7.38 (app s, 2H), 6.95-6.93 (m, 1H), 6.90 (d, 1H,J=8.2 Hz), 6.83 (d, 1H, J=8.5 Hz), 2.11 (s, 3H). ¹⁹F NMR (DMSO-d6): δ−118.78 (s). LCMS: rt 4.60 min (A), purity 97%, MS (m/e) 304 (MH⁺).

6-(2-(3-Fluorophenyl)pyridin-3-yl)-1H-indazole (Compound 100). LCMS: rt4.70 min (A), purity 97%, MS (m/e) 290 (MH⁺).

6-(2-(4-Fluorophenyl)pyridin-3-yl)-1H-indazole (Compound 101). ¹H NMR(DMSO-d6): δ 13.10 (s, 1H), 8.67 (dd, 1H, J=1.7 and 4.7 Hz), 8.03 (s,1H), 7.88 (dd, 1H, J=1.4 and 7.6 Hz), 7.64 (d, 1H, J=7.2 Hz), 7.48 (dd,1H, J=4.9 and 7.9 Hz), 7.38 (s, 1H), 7.34-7.30 (m, 2H), 7.04 (app t, 2H,J=8.8 Hz), 6.83 (d, 1H, J=8.5 Hz). ¹⁹F NMR (DMSO-d6): δ −114.29 (s).LCMS: rt 4.27 min, purity 97%, MS (m/e) 290 (MH⁺).

6-(2-m-Tolylpyridin-3-yl)-1H-indazole (Compound 102). LCMS: rt 4.00 min(A), purity 97%, MS (m/e) 286 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)benzo[d]oxazol-2(3H)-one(Compound 103). LCMS: rt 4.68 min (A), purity 97%, MS (m/e) 321 (MH⁺).

3-(Benzo[d][1,3]dioxol-6-yl)-2-(2-fluorophenyl)pyridine (Compound 104).LCMS: rt 5.39 min (B), purity 97%, MS (m/e) 294 (MH⁺).

3-(Benzo[d][1,3]dioxol-6-yl)-2-(3,4-difluorophenyl)pyridine (Compound105). LCMS: rt 6.10 min (B), purity 97%, MS (m/e) 312 (MH⁺).

3-(Benzo[d][1,3]dioxol-6-yl)-2-(4-fluoro-3-methylphenyl)pyridine(Compound 106). ¹H NMR (DMSO-d6): δ 8.71 (dd, 1H, J=1.4 and 4.9 Hz),8.05 (d, 1H, J=7.6 Hz), 7.65 (dd, 1H, J=4.9 and 7.9 Hz), 7.39 (d, 1H,J=7.6 Hz), 7.07 (d, 2H, J=7.6 Hz), 6.87 (d, 1H, J=8.2 Hz), 6.76 (d, 1H,J=1.4 Hz), 6.63 (dd, 1H, J=1.4 and 8.2 Hz), 6.01 (s, 2H), 2.19 (s, 3H).¹⁹F NMR (DMSO-d6): δ −114.29 (s). LCMS: rt 5.43 min (B), purity 97%, MS(m/e) 308 (MH⁺).

3-(Benzo[d][1,3]dioxol-6-yl)-2-(3-fluorophenyl)pyridine (Compound 107).LCMS: rt 5.61 min (B), purity 97%, MS (m/e) 294 (MH⁺).

3-(Benzo[d][1,3]dioxol-6-yl)-2-(4-fluorophenyl)pyridine (Compound 108).LCMS: rt 5.10 min (B), purity 97%, MS (m/e) 294 (MH⁺).

3-(Benzo[d][1,3]dioxol-6-yl)-2-m-tolylpyridine (Compound 109). LCMS: rt4.78 min (B), purity 97%, MS (m/e) 290 (MH⁺).

3-(Benzo[d][1,3]dioxol-6-yl)-2-(2-fluoro-5-methylphenyl)pyridine(Compound 110). LCMS: rt 5.79 min (B), purity 97%, MS (m/e) 308 (MH⁺).

2-(3-(1H-Indazol-5-yl)pyridin-2-yl)benzonitrile (Compound 111). LCMS: rt4.28 min (B), purity 97%, MS (m/e) 297 (MH⁺).

3-(3-(1H-Indazol-5-yl)pyridin-2-yl)benzonitrile (Compound 112). LCMS: rt4.42 min (B), purity 97%, MS (m/e) 297 (MH⁺).

4-(3-(1H-Indazol-5-yl)pyridin-2-yl)benzonitrile (Compound 113). LCMS:rt4.50 min (B), purity 97%, MS (m/e) 297 (MH⁺).

4-(3-(1H-Indazol-5-yl)pyridin-2-yl)-2-fluorobenzonitrile (Compound 114).LCMS: rt5.11 min (B), purity 97%, MS (m/e) 315 (MH⁺).

5-(2-(4-(Trifluoromethyl)phenyl)pyridin-3-yl)-1H-indazole (Compound115). ¹H NMR (DMSO-d6): δ 133.18 (s, 1H), 8.69 (dd, 1H, J=1.4 and 4.7Hz), 8.04 (s, 1H), 7.90 (dd, 1H, J=1.4 and 7.9 Hz), 7.68 (s, 1H),7.59-7.47 (m, 5H), 7.42 (d, 1H, J=8.8 Hz), 7.02 (dd, 1H, J=1.4 and 8.8Hz). LCMS: rt 5.47 min (B), purity 97%, MS (m/e) 340 (MH⁺).

5-(2-(3-Methoxyphenyl)pyridin-3-yl)-1H-indazole (Compound 117). ¹H NMR(DMSO-d6): δ 13.02 (s, 1H), 8.64 (dd, 1H, J=1.4 and 4.8 Hz), 8.03 (s,1H), 7.84 (d, 1H, J=7.9 Hz), 7.65 (s, 1H), 7.45 (dd, 1H, J=4.7 and 7.6Hz), 7.40 (d, 1H, J=8.5 Hz) 7.08 (t, 1H, J=7.9 Hz), 7.03 (d, 1H, J=8.5Hz), 6.86 (m, 3H), 3.68 (s, 3H). LCMS: rt 3.49 min (B), purity 97%, MS(m/e) 302 (MH⁺).

5-(2-(4-Methoxyphenyl)pyridin-3-yl)-1H-indazole (Compound 118). LCMS: rt2.99 min (B), purity 97%, MS (m/e) 302 (MH⁺).

5-(2-(3,4-Dimethoxyphenyl)pyridin-3-yl)-1H-indazole (Compound 119).LCMS: rt 2.85 min (B), purity 97%, MS (m/e) 332 (MH⁺).

3-(3-(1H-Indazol-5-yl)pyridin-2-yl)phenol (Compound 120). ¹H NMR(DMSO-d6): δ 13.10 (s, 1H), 8.61 (dd, 1H, J=1.7 and 4.7 Hz), 8.03 (s,1H), 7.82 (dd, 1H, J=1.7 and 7.6 Hz), 7.65 (s, 1H), 7.43 (dd, 1H, J=4.7and 7.6 Hz), 7.39 (d, 1H, J=8.2 Hz), 7.02 (dd, 1H, J=1.4 and 8.5 Hz),6.94 (t, 1H, J=7.6 Hz), 6.77 (s, 1H), 6.59 (dd, 2H, J=2.0 and 7.6 Hz).LCMS: rt 2.63 min (B), purity 97%, MS (m/e) 288 (MH⁺).

4-(3-(1H-Indazol-5-yl)pyridin-2-yl)phenol (Compound 121). LCMS: rt 2.27min (B), purity 97%, MS (m/e) 288 (MH⁺).

4-(3-(1H-Indazol-5-yl)pyridin-2-yl)-2-methylphenol (Compound 122). LCMS:rt 2.42 min (B), purity 97%, MS (m/e) 302 (MH⁺).

5-(2-(3,5-dimethoxyphenyl)pyridin-3-yl)-1H-indazole (Compound 123).LCMS: rt 3.79 min (B), purity 97%, MS (m/e) 332 (MH⁺).

5-(2-(4-Fluoro-3-methoxyphenyl)pyridin-3-yl)-1H-indazole (Compound 124).¹H NMR (DMSO-d6): δ 13.01 (s, 1H), 8.65 (dd, 1H, J=4.4 Hz), 8.04 (s,1H), 7.85 (dd, 1H, J=1.7 and 7.9 Hz), 7.67 (s, 1H), 7.45 (dd, 1H, J=4.7and 7.9 Hz), 7.44 (d, 1H, J=8.2 Hz), 7.07-6.97 (m, 3H), 6.82-6.77 (m,1H), 3.49 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −117.70 (q, H=4.2 Hz). LCMS: rt3.95 min (B), purity 97%, MS (m/e) 320 (MH⁺).

5-(2-(3-Methoxy-4-methylphenyl)pyridin-3-yl)-1H-indazole (Compound 125).LCMS: rt 4.86 min (B), purity 97%, MS (m/e) 316 (MH⁺).

5-(2-(4-(Benzyloxy)-3-methoxyphenyl)pyridin-3-yl)-1H-indazole (Compound126). ¹H NMR (DMSO-d6): δ 13.01 (s, 1H), 8.61 (d, 1H, J=4.7 Hz), 8.05(s, 1H), 7.79 (d, 1H, J=7.9 Hz), 7.67 (s, 1H), 7.43-7.29 (m, 7H), 7.04(d, 1H, J=9.1 Hz), 6.91 (s, 1H), 6.87 (d, 1H, J=7.9 Hz), 6.78 (d, 1H,J=9.1 Hz), 4.98 (s, 2H), 3.49 (s, 3H). LCMS: rt 4.51 min (B), purity97%, MS (m/e) 408 (MH⁺).

5-(2-(4-Aminosulfonylphenyl)pyridin-3-yl)-1H-indazole (Compound 127).LCMS: rt 3.40 min (B), purity 97%, MS (m/e) 351 (MH⁺).

5-(2-(3-Amino sulfonylphenyl)pyridin-3-yl)-1H-indazole (Compound 128).LCMS: rt 3.36 min (B), purity 97%, MS (m/e) 351 (MH⁺).

6-(2-(3,4-Difluorophenyl)pyridin-3-yl)-1-methyl-1H-indazole (Compound129). LCMS: rt 6.10 min (A), purity 97%, MS (m/e) 322 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-methyl-1H-indazole(Compound 130). ¹H NMR (DMSO-d6): δ 8.72 (dd, 1H, J=1.4 and 4.9 Hz),8.04 (dd, 1H, J=1.4 and 7.9 Hz), 8.01 (s, 1H), 7.67 (s, 1H), 7.60 (dd,2H, J=4.8 and 7.9 Hz), 7.41 (d, 1H, J=7.6 Hz), 7.01-6.99 (m, 2H), 6.74(d, 1H, J=8.2 Hz), 4.00 (s, 3H), 2.13 (s, 3H). ¹⁹F NMR (DMSO-d6): δ−117.88 (s). LCMS: rt 5.55 min (A), purity 97%, MS (m/e) 318 (MH⁺).

1-Methyl-6-(2-m-tolylpyridin-3-yl)-1H-indazole (Compound 131). LCMS: rt5.25 min (A), purity 97%, MS (m/e) 300 (MH⁺).

6-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)-1-methyl-1H-indazole(Compound 132). LCMS: rt 5.78 min (A), purity 97%, MS (m/e) 318 (MH⁺).

3-(3-(1-Methyl-1H-indazol-6-yl)pyridin-2-yl)benzonitrile (Compound 133).LCMS: rt 5.86 min (A), purity 97%, MS (m/e) 311 (MH⁺).

6-(2-(3-methoxyphenyl)pyridin-3-yl)-1-methyl-1H-indazole (Compound 134).LCMS: rt 5.10 min (A), purity 97%, MS (m/e) 316 (MH⁺).

6-(2-(4-Fluoro-3-methoxyphenyl)pyridin-3-yl)-1-methyl-1H-indazole(Compound 135). LCMS: rt 5.41 min (A), purity 97%, MS (m/e) 334 (MH⁺).

3-(3-(1-Methyl-1H-indazol-6-yl)pyridin-2-yl)phenol (Compound 136). LCMS:rt 4.41 min (A), purity 97%, MS (m/e) 302 (MH⁺).

6-(2-(3,4-Difluorophenyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Compound 137). LCMS: rt 4.83 min (A), purity 97%, MS (m/e) 309 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Compound 138). ¹H NMR (DMSO-d6): δ 8.75 (dd, 1H, J=1.5 and 5.1 Hz),8.27 (app s 1H), 8.19 (d, 1H, J=4.8 Hz), 8.09 (dd, 1H, J=1.5 and 4.8Hz), 7.93 (t, 1H, J=0.79 Hz), 7.62 (dd, 1H, J=4.8 and 8.1 Hz), 7.39 (d,1H, J=0.79 Hz), 7.62 (dd, 1H, J=4.8 and 8.1 Hz), 6.98-6.92 (m, 2H), 2.13(s, 3H). LCMS: rt 4.35 min (A), purity 97%, MS (m/e) 305 (MH⁺).

6-(2-m-Tolylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine (Compound 139).LCMS: rt 4.00 min (A), purity 97%, MS (m/e) 287 (MH⁺).

6-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Compound 140). LCMS: rt 4.60 min (A), purity 97%, MS (m/e) 305 (MH⁺).

3-(3-(1H-Pyrazolo[4,3-b]pyridin-6-yl)pyridin-2-yl)benzonitrile (Compound141). LCMS: rt 4.48 min, purity 97%, MS (m/e) 298 (MH⁺).

6-(2-(3-Methoxyphenyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine (Compound142). LCMS: rt 3.90 min (A), purity 97%, MS (m/e) 303 (MH⁺).

6-(2-(4-Fluoro-3-methoxyphenyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Compound 143). LCMS: rt 4.21 min (A), purity 97%, MS (m/e) 321 (MH⁺).

3-(3-(1H-Pyrazolo[4,3-b]pyridin-6-yl)pyridin-2-yl)phenol (Compound 144).LCMS: rt 3.11 min (A), purity 97%, MS (m/e) 289 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-methyl-1H-indazole(Compound 145). ¹H NMR (DMSO-d6): δ 8.71 (dd, 1H, J=0.4 and 4.9 Hz),8.06 (dd, 1H, J=1.4 and 7.9 Hz), 8.03 (s, 1H), 7.68 (s, 1H), 7.63 (dd,1H, J=4.9 and 7.9 Hz), 7.53 (d, 1H, J=8.8 Hz), 7.41 (d, 1H, J=7.9 Hz),7.07 (dd, 1H, J=1.4 and 8.8 Hz), 6.97-6.95 (m, 2H), 4.01 (s, 3H), 2.14(s, 3H). ¹⁹F NMR (DMSO-d6): δ −118.70 (s). LCMS: rt 5.36 min (A), purity97%, MS (m/e) 318 (MH⁺).

1-Methyl-5-(2-m-tolylpyridin-3-yl)-1H-indazole (Compound 146). LCMS: rt5.11 min (A), purity 97%, MS (m/e) 300 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-methyl-1H-indazole(Compound 147). ¹H NMR (DMSO-d6): δ 8.69 (dd, 1H, J=1.4 and 4.7 Hz),8.07 (dd, 1H, J=1.7 and 7.9 Hz), 7.68 (s, 1H), 7.63-7.58 (m, 1H), 7.38(d, 1H, J=7.3 Hz), 7.30 (d, 1H, J=8.8 Hz), 6.99-6.91 (m, 3H), 2.44 (s,3H), 2.13 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −117.70 (s). LCMS: rt 5.01 min(A), purity 97%, MS (m/e) 318 (MH⁺).

3-Methyl-5-(2-m-tolylpyridin-3-yl)-1H-indazole (Compound 148). LCMS: rt4.78 min (A), purity 97%, MS (m/e) 300 (MH⁺).

5-(2-(3-Ethylphenyl)pyridin-3-yl)-1H-indazole (Compound 149). ¹H NMR(DMSO-d6): δ 8.64 (dd, 1H, J=1.4 and 4.7 Hz), 8.02 (s, 1H), 7.84 (dd,1H, J=1.4 and 7.6 Hz), 7.63 (s, 1H), 7.44 (dd, 1H, J=4.9 and 8.7 Hz),7.39 (d, 1H, J=8.8 Hz), 7.10 (s, 1H), 7.09 (s, 1H), 7.06-7.04 (m, 1H),7.01 (dd, 1H, J=1.4 and 8.7 Hz), 2.42 (qt, 2H, J=7.6 Hz), 0.86 (t, 3H,J=7.6 Hz). LCMS: rt 4.93 min (A), purity 97%, MS (m/e) 300 (MH⁺).

5-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-1H-indazole (Compound 150). ¹HNMR (DMSO-d6): δ 13.02 (s, 1H), 8.63 (dd, 1H, J=1.4 and 4.8 Hz), 8.03(s, 1H), 7.82 (dd, 1H, J=7.6 Hz), 7.62 (s, 1H), 7.43 (dd, 1H, J=4.8 and7.6 Hz), 7.40 (d, 1H, J=7.9 Hz), 7.07 (s, 1H), 7.05 (s, 1H), 7.02-6.94(m, 2H), 6.86 (s, 1H), 1.76-1.67 (m, 1H), 0.76-0.68 (m, 2H), 0.24-0.19(m, 2H). LCMS: rt 4.96 min (A), purity 97%, MS (m/e) 312 (MH⁺).

5-(2-(3-Ethylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (Compound151). ¹H NMR (DMSO-d6): δ 13.58 (s, 1H), 8.69 (dd, 1H, J=1.4 and 4.7Hz), 8.15 (dd, 1H, J=0.5 and 2.0 Hz), 7.93 (dd, 1H, J=1.4 and 7.9 Hz),7.50 (d, 1H, J=4.8 and 7.9 Hz), 7.16-7.05 (m, 4H), 2.41 (qt, 2H, J=7.3Hz), 0.86 (t, 3H, J=7.3 Hz). LCMS: rt 4.48 min (A), purity 97%, MS (m/e)301 (MH⁺).

5-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 152). ¹H NMR (DMSO-d6): δ 13.6 (s, 1H), 8.75 (dd, 1H, J=1.4and 4.7 Hz), 8.19 (d, 1H, J=7.9 Hz), 8.17 (d, 1H, J=5.3 Hz), 7.98 (d,1H, J=7.6 Hz), 7.56 (dd, 1H, J==4.8 and 7.9 Hz), 7.18-7.04 (m, 3H), 6.92(s, 1H), 1.85-1.78 (m, 2H), 0.84-0.78 (m, 2H), 0.33-0.12 (m, 2H). LCMS:rt 4.56 min, purity 97%, MS (m/e) 313 (MH⁺).

5-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 153). ¹H NMR (DMSO-d6): δ 13.6 (s, 1H), 8.70 (dd, 1H, J=1.4and 4.7 Hz), 8.22 (d, 1H, J=1.7 Hz), 8.08 (d, 1H, J=1.2 Hz), 8.03 (d,1H, J=1.4 Hz), 7.96 (dd, 1H, J=1.4 and 7.9 Hz), 7.56 (dd, 1H, J=4.9 and7.9 Hz), 7.35 (dd, 1H, 1.4 and 4.7 Hz), 7.15-7.11 (m, 1H), 6.81 (t, 1H,J=8.8 Hz), 2.27 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −120.40 (s). LCMS: rt 4.71min (A), purity 97%, MS (m/e) 305 (MH⁺).

3-(3-(1H-Pyrazolo[3,4-b]pyridin-5-yl)pyridin-2-yl)benzonitrile (Compound154). LCMS: rt 4.61 min (A), purity 97%, MS (m/e) 298 (MH⁺).

5-(2-(3-Methoxyphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (Compound155). ¹H NMR (DMSO-d6): δ 13.58 (s, 1H), 8.71 (dd, 1H, J=1.7 and 4.7Hz), 8.18 (d, 1H, J=2.0 Hz), 8.13 (d, 1H, J=2.0 Hz), 8.12 (s, 1H), 7.97(dd, 1H, J=1.7 and 7.6 Hz), 7.54 (dd, 1H, J=4.6 and 7.6 Hz), 7.12 (t,1H, J=7.9 Hz), 6.89-6.88 (app m, 1H), 6.82 (dd, 1H, J=2.3 and 8.5 Hz),6.78 (d, 1H, J=8.5 Hz), 3.56 (s, 3H). LCMS: rt 3.96 min (A), purity 97%,MS (m/e) 303 (MH⁺).

3-(3-(1H-Pyrazolo[3,4-b]pyridin-5-yl)pyridin-2-yl)phenol (Compound 156).LCMS: rt 3.30 min, purity 97%, MS (m/e) 289 (MH⁺).

5-(2-(4-Fluoro-3-methoxyphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 157). LCMS: rt 4.26 min (A), purity 97%, MS (m/e) 321 (MH⁺).

5-(3-(1H-Pyrazolo[3,4-b]pyridin-5-yl)pyridin-2-yl)-2-fluorobenzonitrile(Compound 158). LCMS: rt 5.18 min (A), purity 97%, MS (m/e) 316 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)benzo[d]thiazole (Compound159). ¹H NMR (DMSO-d6): δ 9.37 (d, 1H, J=2.1 Hz), 8.66 (app d, 1H, J=4.7Hz), 8.08 (s, 1H), 7.96 (d, 1H, J=8.5 Hz), 7.88 (d, 1H, J=7.6 Hz), 7.48(dd, 1H, J=4.7 and 7.6 Hz), 7.36 (d, 1H, J=7.9 Hz), 7.22 (dd, 1H, J=0.88and 8.5 Hz), 6.93-6.87 (m, 2H), 2.11 (s, 3H). ¹⁹F NMR (DMSO-d6): δ−118.59 (s). LCMS: rt 5.51 min (A), purity 97%, MS (m/e) 321 (MH⁺).

6-(2-m-Tolylpyridin-3-yl)benzo[d]thiazole (Compound 160). ¹H NMR(DMSO-d6): δ 9.36 (d, 1H, J=2.1 Hz), 8.67 (app d, 1H, J=4.7 Hz), 8.07(s, 1H), 7.93 (d, 1H, J=8.2 Hz), 7.88 (d, 1H, J=8.2 Hz), 7.47 (dd, 1H,J=4.9 and 7.9 Hz), 7.25-7.20 (m, 2H), 7.03-6.99 (m, 2H), 6.91 (d, 1H,J=4.9 Hz), 2.18 (s, 3H). LCMS: rt 5.15 min (A), purity 97%, MS (m/e) 303(MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine(Compound 161). ¹H NMR (DMSO-d6): δ 9.24 (s, 1H), 8.71 (dd, 1H, J=1.4and 4.7 Hz), 8.63 (s, 1H), 7.93 (d, 1H, J=7.6 Hz), 7.61 (d, 1H, J=9.4Hz), 7.52 (dd, 1H, J=4.7 and 7.7 Hz), 7.43 (d, 1H, J=7.6 Hz), 7.12-7.08(m, 1H), 6.99 (app t, 1H, J=9.3 Hz), 6.90 (d, 1H, J=9.7 Hz), 2.16 (s,3H). ¹⁹F NMR (DMSO-d6): δ −117.98 (s). LCMS: rt 4.20 min (A), purity97%, MS (m/e) 305 (MH⁺).

6-(2-m-Tolylpyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (Compound 162).¹H NMR (DMSO-d6): δ 9.23 (s, 1H), 8.72 (dd, 1H, J=1.4 and 7.9 Hz), 8.62(s, 1H), 7.93 (dd, 1H, J=1.4 and 7.9 Hz), 7.58 (d, 1H, J=9.4 Hz), 7.51(dd, 1H, J=4.9 and 7.9 Hz), 7.32 (s, 1H), 7.12 (app d, 1H, J=4.9 Hz),7.11 (s, 1H), 7.07-7.05 (app m, 1H), 6.89 (dd, 1H, J=1.4 and 8.7 Hz),2.23 (s, 3H). LCMS: rt 3.76 min (A), purity 97%, MS (m/e) 287 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)benzo[d]thiazole (Compound163). ¹H NMR (DMSO-d6): δ 9.38 (d, 1H, J=1.7 Hz), 8.66 (dd, 1H, J=1.4and 4.7 Hz), 8.06 (d, 1H, J=8.5 Hz), 7.95 (s, 1H), 7.90 (dd, 1H, J=1.4and 7.9 Hz), 7.49 (dd, 1H, J=4.7 and 7.9 Hz), 7.37 (d, 1H, J=7.6 Hz),7.20 (d, 1H, J=8.2 Hz), 6.97-6.87 (m, 2H), 2.12 (s, 3H). ¹⁹F NMR(DMSO-d6): δ −118.65 (s). LCMS: rt 5.56 min (A), purity 97%, MS (m/e)321 (MH⁺).

5-(2-m-Tolylpyridin-3-yl)benzo[d]thiazole (Compound 164). LCMS: rt 5.23min (A), purity 97%, MS (m/e) 303 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 165). ¹H NMR (DMSO-d6): δ 8.69 (s, 2H), 8.02 (s, 1H), 7.92 (d,1H, J=1.5 and 7.6 Hz), 7.72 (s, 1H), 7.52-7.49 (m, 2H), 7.44 (d, 1H,J=7.2 Hz), 7.09-7.04 (m, 1H), 7.00-6.94 (m, 2H), 2.16 (s, 3H). ¹⁹F NMR(DMSO-d6): δ −118.16 (s). LCMS: rt 3.56 min (A), purity 97%, MS (m/e)304 (MH⁺).

6-(2-m-Tolylpyridin-3-yl)imidazo[1,2-a]pyridine (Compound 166). ¹H NMR(DMSO-d6): δ 8.68 (d, 1H, J=5.7 Hz), 8.57 (s, 1H), 7.92-7.89 (m, 2H),7.55 (s, 1H), 7.48 (dd, 1H, J=4.9 and 8.1 Hz), 7.38 (d, 1H, J=8.3 Hz),7.31 (s, 1H), 7.10-7.04 (app m, 2H), 7.04-7.02 (app m, 1H), 6.79 (d, 1H,J=8.4 Hz), 2.22 (s, 3H). LCMS: rt 3.05 min (A), purity 97%, MS (m/e) 286(MH⁺).

5-(2-(3-Isopropylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 167). LCMS: rt 4.81 min (A), purity 97%, MS (m/e) 315 (MH⁺).

5-(2-(3-tert-Butylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 168). LCMS: rt 5.08 min (A), purity 97%, MS (m/e) 329 (MH⁺).

5-(2-(3-Biphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (Compound169). LCMS: rt 5.30 min (A), purity 97%, MS (m/e) 349 (MH⁺).

5-(2-(3-Cyclopentenylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 170). LCMS: rt 5.33 min (A), purity 97%, MS (m/e) 339 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-6-methyl-1H-indazole(Compound 173). ¹H NMR (DMSO-d6): δ 8.75 (dd, 1H, J=1.4 and 4.9 Hz),7.98 (s, 1H), 7.93 (dd, 1H, J=1.4 and 7.6 Hz), 7.61 (dd, 1H, J=4.9 and7.6 Hz), 7.53 (s, 1H), 7.37 (d, 1H, J=7.6 Hz), 7.33 (s, 1H), 7.02-6.97(m, 1H), 6.98 (t, 1H, J=8.8 Hz), 2.07 (s, 3H), 1.93 (s, 3H). ¹⁹F NMR(DMSO-d6): δ −117.35 (s). LCMS: rt 5.01 min(A), purity 97%, MS (m/e) 318(MH⁺).

6-Methyl-5-(2-m-tolylpyridin-3-yl)-1H-indazole (Compound 174). LCMS: rt4.73 min (A), purity 97%, MS (m/e) 300 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-7-methyl-1H-indazole(Compound 175). ¹H NMR (DMSO-d6): δ 8.69 (d, 1H, J=1.7 and 4.9 Hz), 8.08(d, 1H, J=7.6 Hz), 8.02 (s, 1H), 7.64 (app t, 1H, J=7.6 Hz), 7.43-7.41(app m, 2H), 7.01-6.91 (m, 3H), 2.40 (s, 3H), 2.13 (s, 3H). ¹⁹F NMR(DMSO-d6): δ −117.30 (s). LCMS: rt 4.80 min, purity 97%, MS (m/e) 318(MH⁺).

7-Methyl-5-(2-m-tolylpyridin-3-yl)-1H-indazole (Compound 176). ¹H NMR(DMSO-d6): δ 13.04 (s, 1H), 8.73 (d, 1H, J=2.8 Hz), 8.14 (d, 1H, J=7.9Hz), 8.00 (s, 1H), 7.69 (dd, 1H, J=4.9 and 7.9 Hz), 7.41 (s, 1H), 7.31(s, 1H), 7.14-7.06 (m, 2H), 6.97 (d, 1H, J=7.2 Hz), 6.90 (s, 1H), 2.38(s, 3H), 2.21 (s, 3H). LCMS: rt 5.03 min (A), purity 97%, MS (m/e) 300(MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-benzo[d]imidazole(Compound 177). ¹H NMR (DMSO-d6): δ 8.62 (d, 1H, J=0.2 and 3.7 Hz), 8.24(s, 1H), 7.83 (dd, 1H, J=1.5 and 7.6 Hz), 7.49 (d, 1H, =8.1 Hz), 7.45(d, 1H, J=4.7 Hz), 7.43-7.42 (m, 1H), 7.36 (d, 1H, J=7.3 Hz), 6.96-6.84(m, 3H), 2.11 (s, 3H).). ¹⁹F NMR (DMSO-d6): δ −118.99 (s). LCMS: rt 3.41min, purity 97%, MS (m/e) 304 (MH⁺).

6-(2-m-Tolylpyridin-3-yl)-1H-benzo[d]imidazole (Compound 178). ¹H NMR(DMSO-d6): δ 8.64 (d, 1H, J=5.1 Hz), 8.42 (s, 1H), 7.84 (d, 1H, J=7.3Hz), 7.51 (d, 1H, J=8.5 Hz), 7.44 (dd, 1H, J=4.5 and 7.5 Hz), 7.26 (s,1H), 7.02 (s, 2H), 6.98 (d, 1H, J=7.6 Hz), 6.90 (d, 1H, J=7.3 Hz), 2.18(s, 3H). LCMS: rt 1.75 min (A), purity 97%, MS (m/e) 286 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)benzo[d]oxazole (Compound180). ¹H NMR (DMSO-d6): δ 8.71 (d, 1H, J=2.0 Hz), 8.66 (app d, 1H, J=2.8Hz), 7.87 (d, 1H, J=7.3 Hz), 7.69 (d, 1H, J−8.8 Hz), 7.68 (app s, 1H),7.47 (dd, 1H, J=4.8 and 7.9 Hz), 7.33 (d, 1H, J=7.0 Hz), 7.12 (dd, 1H,J=1.7 and 8.4 Hz), 6.93-6.87 (m, 2H), 2.12 (s, 3H). ¹⁹F NMR (DMSO-d6): δ−118.61 (s). LCMS: rt 5.33 min (A), purity 97%, MS (m/e) 305 (MH⁺).

6-(2-m-Tolylpyridin-3-yl)benzo[d]oxazole (Compound 181). LCMS: rt 4.90min (A), purity 92%, MS (m/e) 287 (MH⁺).

2-Ethyl-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazole(Compound 182). ¹H NMR (DMSO-d6): δ 8.69 (d, 1H, J=4.9 Hz), 8.37 (s,1H), 8.02 (d, 1H, J=7.9 Hz), 7.63 (s, 1H), 7.60 (dd, 1H, J=5.2 and 7.6Hz), 7.45 (app t 2H, J=9.1 Hz), 7.02-6.92 (app m, 2H), 6.88 (d, 1H,J=8.1 Hz), 4.35 (qt, 2H, J=7.0 Hz), 2.14 (s, 3H), 1.48 (t, 3H, J=7.0Hz). ¹⁹F NMR (DMSO-d6): δ −117.62 (s). LCMS: rt 5.30 min (A), purity97%, MS (m/e) 332 (MH⁺).

2-Ethyl-5-(2-m-tolylpyridin-3-yl)-2H-indazole (Compound 183). LCMS: rt5.06 min (A), purity 97%, MS (m/e) 314 (MH⁺).

1-Ethyl-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole(Compound 184). ¹H NMR (DMSO-d6): δ 8.70 (dd, 1H, J=1.7 and 4.9 Hz),8.08-8.04 (m, 2H), 7.68 (d, 1H, J=0.9 Hz), 7.66-7.55 (m, 1H), 7.57 (d,1H, J=8.8 Hz), 7.40 (d, 1H, J=7.9 Hz), 7.05 (dd, 1H, J=1.8 and 8.8 Hz),7.03-6.92 (m, 2H), 4.39 (qt, 2H, J−7.0 Hz), 2.13 (s, 3H), 1.35 (t, 3H,J=7.3 Hz). ¹⁹F NMR (DMSO-d6): δ −117.42 (s). LCMS: rt 5.71 min(A),purity 97%, MS (m/e) 332 (MH⁺).

1-Ethyl-5-(2-m-tolylpyridin-3-yl)-1H-indazole (Compound 185). LCMS: rt5.43 min (A), purity 97%, MS (m/e) 314 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 191). ¹H NMR (DMSO-d6): δ 9.01 (t, 1H, J=0.77 Hz), 8.71 (dd,1H, J=1.7 and 4.7 Hz), 8.50 (s, 1H), 8.00 (dd, 1H, J=1.7 and 7.9 Hz),7.70 (dd, 1H, J=1.7 and 9.1 Hz), 7.51 (dd, 1H, J=4.6 and 7.6 Hz), 7.43(dd, 1H, J=1.7 and 7.9 Hz), 7.23 (dd, 1H, J=1.7 and 9.3 Hz), 7.08-7.04(m, 1H), 6.97 (app t, 1H, J=9.3 Hz), 2.16 (s, 3H). ¹⁹F NMR (DMSO-d6): δ−118.12 (s). LCMS: 4.76 min (A), purity 97%, MS (m/e) 305 (MH⁺).

6-(2-m-Tolylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (Compound 192).¹H NMR (DMSO-d6): δ 8.98 (s, 1H), 8.72 (dd, 1H, J=1.7 and 4.7 Hz), 8.49(s, 1H), 8.01 (d, 1H, J=1.7 and 7.9 Hz), 7.68 (d, 1H, J=9.2 Hz),7.54-7.49 (m, 1H), 7.30 (s, 1H), 7.23 (dd, 1H, J=1.4 and 7.6 Hz),7.10-7.09 (app m, 2H), 7.03-7.02 (m, 1H), 2.22 (s, 3H). ¹⁹F NMR(DMSO-d6): δ −118.31 (s). LCMS: rt 4.31 min (A), purity 95%, MS (m/e)287 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)H-imidazo[1,2-a]pyridine(Compound 193). ¹H NMR (DMSO-d6): δ 8.68 (dd, 1H, J=1.7 and 4.7 Hz),8.53 (app s, 1H), 7.91 (dd, 1H, J=1.6 and 9.3 Hz), 7.90 (s, 1H), 7.53(d, 1H, J=1.2 Hz), 7.46 (dd, 1H, J=4.6 and 7.6 Hz), 7.38 (dd, 1H, J=9.3Hz), 7.12-7.04 (m, 2H), 7.02-6.99 (m, 2H), 6.78 (dd, 1H, J=1.7 and 9.3Hz), 1.81-1.76 (m, 1H), 0.79-0.75 (m, 2H), 0.36-0.32 (m, 2H). LCMS: rt4.73 min (A), purity 97%, MS (m/e) 312 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)benzo[d]thiazole (Compound 194).¹H NMR (DMSO-d6): δ 9.19 (s, 1H), 8.68 (dd, 1H, J=1.4 and 4.7 Hz), 8.05(d, 1H, J=1.2 Hz), 7.96 (d, 1H, J=8.5 Hz), 7.86 (app dd, 1H, J=1.4 and7.6 Hz), 7.47 (dd, 1H, J=4.7 and 7.6 Hz), 7.21 (dd, 1H, J=1.7 and 7.6Hz), 7.09-7.07 (m, 2H), 6.99-6.97 (m, 1H), 6.84 (s, 1H), 1.76-1.71 (m,1H), 0.75-0.69 (m, 2H), 0.24-0.19 (m, 2H). LCMS: rt 5.53 min (A), purity97%, MS (m/e) 329 (MH⁺).

5-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)-1H-indazole (Compound197). ¹H NMR (DMSO-d6): δ 13.02 (s, 1H), 8.70 (dd, 1H, J=1.4 and 4.7Hz), 8.04 (s, 1H), 7.91 (dd, 1H, J=0.7 and 7.6 Hz), 7.68 (s, 1H), 7.63(s, 1H), 7.58 (d, 1H, J=8.2 Hz), 7.54-7.50 (m, 2H), 7.50-7.41 (m, 2H),7.03 (d, 1H, J=8.5 Hz). ¹⁹F NMR (DMSO-d6): δ −61.47. LCMS: rt 5.78 min(A), purity 97%, MS (m/e) 340 (MH⁺).

5-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 198). ¹H NMR (DMSO-d6): δ 13.65 (s, 1H), 8.75 (dd, 1H, J=1.7and 4.7 Hz), 8.20 (d, 1H, J=2.0 Hz), 8.15 (d, 1H, J=1.4 Hz), 8.12 (s,1H), 7.99 (d, 1H, J=1.4 and 7.9 Hz), 7.64-7.44 (m, 5H). ¹⁹F NMR(DMSO-d6): δ −61.40. LCMS: rt 5.55 min (A), purity 97%, MS (m/e) 341(MH⁺).

6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)H-imidazo[1,2-a]pyridine(Compound 199). ¹H NMR (DMSO-d6): δ 8.62 (dd, 1H, J=1.4 and 4.7 Hz),8.06 (s, 1H), 7.65 (dd, 1H, J=1.7 and 8.2 Hz), 7.46-7.42 (m, 3H),7.05-7.04 (m, 2H), 6.97-6.95 (m, 1H), 6.90 (s, 1H), 6.85 (dd, 1H, J=1.4and 8.2 Hz), 3.86 (s, 3H), 1.76-1.69 (m, 1H), 0.84-0.70 (m, 2H),0.28-0.23 (m, 2H). LCMS: rt 4.68 min (A), purity 97%, MS (m/e) 340(MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 200). ¹H NMR (DMSO-d6): δ 8.63 (dd, 1H, J=1.4 and 4.7 Hz),8.12 (s, 1H), 7.85 (dd, 1H, J=1.7 and 8.2 Hz), 7.48-7.42 (m, 3H),7.05-7.04 (app m, 2H), 6.97-6.95 (m, 1H), 6.90 (s, 1H), 6.85 (dd, 1H,J=1.4 and 8.2 Hz), 3.73 (s, 3H), 1.78-1.69 (m, 1H), 0.76-0.70 (m, 2H),0.28-0.23 (m, 2H). LCMS: rt 3.68 min (A), purity 97%, MS (m/e) 326(MH⁺).

5-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 201). ¹H NMR (DMSO-d6): δ 8.63 (dd, 1H, J=1.4 and 4.7 Hz),8.16 (s, 1H), 7.82 (dd, 1H, J=1.4 and 7.6 Hz), 7.82 (dd, 1H, J=1.4 and7.6 Hz), 7.47-7.41 (m, 3H), 7.05-6.67 (m, 5H), 3.81 (s, 3H), 1.78-1.71(m, 1H), 0.78-0.72 (m, 2H), 0.31-0.26 (m, 3H). LCMS: rt 3.76 min (A),purity 97%, MS (m/e) 326 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 202). ¹H NMR (DMSO-d6): δ 8.96 (s, 3H), 8.72 (dd, 1H, J=1.7and 4.9 Hz), 8.50 (s, 1H), 7.99 (dd, 1H, J=1.4 and 7.6 Hz), 7.69 (dd,1H, J=0.9 and 9.1 Hz), 7.52 (dd, 1H, J=4.7 and 7.7 Hz), 7.24 (dd, 1H,J=0.8 and 9.1 Hz), 7.14 (m, 2H), 7.03 (s, 1H), 6.98 (m, 1H), 1.78-1.71(m, 1H), 0.82-0.72 (m, 2H), 0.31-0.30 (m, 2H). LCMS: rt 4.93 min (A),purity 97%, MS (m/e) 313 (MH⁺).

6-(2-(3-Isopropylphenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 204). LCMS: rt 4.16 min (A), purity 97%, MS (m/e) 328 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-1H-benzo[d]imidazole (Compound205). LCMS: rt 3.80 min (A), purity 97%, MS (m/e) 312 (MH⁺).

6-(2-(3-Isopropylphenyl)pyridin-3-yl)-1H-benzo[d]imidazole (Compound206). LCMS: rt 4.06 min (A), purity 97%, MS (m/e) 314 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinoline (Compound 207). ¹HNMR (DMSO-d6): δ 9.11 (dd, 1H, J=1.4 and 4.7 Hz), 8.77 (dd, 2H, J=1.4and 4.9 Hz), 8.20 (d, 1H, 1.4 Hz), 8.13-8.08 (m, 2H), 7.84 (dd, 1H,J=4.8 and 8.2 Hz), 7.66-7.59 (m, 2H), 7.40 (d, 1H, J=7.6 Hz), 6.99-6.90(m, 2H), 2.12 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −117.48 (s). LCMS: rt 4.23min (A), purity 97%, MS (m/e) 315 (MH⁺).

6-(2-m-Tolylpyridin-3-yl)quinoline (Compound 208). ¹H NMR (300 MHz,DMSO-d₆): δ 9.02 (dd, J=4.6, 1.6 Hz, 1H), 8.75 (dd, J=4.9, 1.7 Hz, 1H),8.59 (d, J=7.7 Hz, 1H), 8.09 (d, J=1.9 Hz, 1H), 8.06 (dd, J=7.8, 1.7 Hz,1H), 8.01 (d, J=8.8 Hz, 1H), 7.72 (dd, J=8.3, 4.6 Hz, 1H), 7.61 (dd,J=7.8, 4.9 Hz, 1H), 7.53 (dd, J=8.8, 2.0 Hz, 1H), 7.28 (dd, J=1.5, 0.9Hz, 1H), 7.14-7.01 (m, 2H), 6.96 (ddd, J=6.4, 2.5, 1.4 Hz, 1H), 2.18 (s,3H). LCMS: rt 3.88 min (A), purity 99%, MS (m/e) 297 (MH⁺).

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)isoquinoline (Compound 209).LCMS: rt 4.12 min (A), purity 97%, MS (m/e) 315 (MH⁺).

7-(2-m-Tolylpyridin-3-yl)isoquinoline (Compound 210). ¹H NMR (300 MHz,DMSO-d₆): δ 9.69 (s, 1H), 8.79 (dd, J=4.9, 1.6 Hz, 1H), 8.64 (d, J=6.3Hz, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 8.08 (s, 2H), 7.84-7.50 (m, 2H),7.28 (s, 1H), 7.07 (dt, J=14.8, 7.5 Hz, 2H), 6.96 (d, J=7.2 Hz, 1H),2.19 (s, 3H). LCMS: rt 3.75 min (A), purity 99%, MS (m/e) 296 (MH⁺).

Example 45 Synthetic scheme towards the preparation of6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1-(substituted)-1H-benzo[d]imidazole

Example 466-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole(Compound 35)

Step C:5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenamine

To solution of2-(4-fluoro-3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine (100 mg)in 2 mL THF was added 2-morpholinoethanamine (64 uL) and K₂CO₃ (76 mg).The reaction was heated at 60° C. for 15 hours in a sealed vial. Thereaction mixture was cooled to room temperature, concentrated by rotaryevaporation under vacuum and partitioned the concentrate betweenCH₂Cl₂/water. The organic layer was separated, dried with anhydrousNa₂SO₄, filtered and evaporated. The crude residue of5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenaminewas used in the next step with no further purification.

Step D: 5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenamine

The above residue of5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenaminewas dissolved in 2 mL EtOH and charged with Pd/C (25 mg) and the thereaction was hydrogenated overnight under a hydrogen balloon atmosphere.The reaction was filtered through a bed of celite and evaporated.Subsequently the crude containing5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenaminewas used in the next with no further purification.

Step E: 6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole

The above residue containing5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenaminewas added DMA (1 mL), triethyl orthoformate (250 uL) and treated withone drop of concentrated HCl. The homogeneous solution was heated at 65°C. for 15 hours in a sealed vial. The reaction was cooled and thevolatiles were removed with a stream of nitrogen gas. The residue wastriturated with aq. NaHCO₃, resulting solid collected by filtration andpurified by HPLC to yield 25 mg of the desired product6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole. ¹H NMR (DMSO-d6): δ 8.58 (dd, J=4.7, 1.6Hz, 1H), 8.15 (s, 1H), 7.84 (dd, J=7.8, 1.6 Hz, 1H), 7.56 (d, J=8.3 Hz,1H), 7.43 (dd, J=7.8, 4.7 Hz, 1H), 7.28 (d, J=4.8 Hz, 2H), 7.05 (dd,J=8.3, 1.5 Hz, 1H), 7.03-6.75 (m, 2H), 4.19 (t, J=6.4 Hz, 2H), 3.55-3.36(m, 4H), 2.44-2.15 (m, 6H), 2.06 (s, 3H). MS (m/e): 417 (MH⁺).

Example 476-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-isopropyl-1H-benzo[d]imidazole(Compound 48)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole,the reaction of2-(4-fluoro-3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine andpropan-2-amine yielded6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-isopropyl-1H-benzo[d]imidazole.¹H NMR (DMSO-d6): δ 9.58 (s, 1H), 8.75 (d, J=4.9 Hz, 1H), 8.11 (d, J=7.8Hz, 1H), 7.89 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.65 (dd, J=7.8, 5.0 Hz,1H), 7.43-7.29 (m, 2H), 7.15-6.87 (m, 2H), 4.98-4.79 (m, 1H), 2.11 (s,3H), 1.48 (d, J=6.6 Hz, 6H). MS (m/e): 346 (MH⁺).

Example 481-(2-Morpholinoethyl)-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole(Compound 36)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole, the reaction of2-(3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine and2-morpholinoethanamine yielded1-(2-Morpholinoethyl)-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole. ¹HNMR (DMSO-d6): δ 9.46 (s, 1H), 8.81 (dd, J=5.0, 1.3 Hz, 1H), 8.23 (dd,J=7.8, 1.3 Hz, 1H), 8.05 (s, 1H), 7.89-7.62 (m, 2H), 7.33 (s, 1H),7.18-7.07 (m, 3H), 6.96 (d, J=7.3 Hz, 1H), 4.88 (m, 2H), 3.84 (s, 4H),3.62 (m, 2H), 3.34 (s, 4H) 2.22 (s, 3H). MS (m/e): 399 (MH⁺).

Example 496-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-benzo[d]imidazole(Compound 37)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole,the reaction of2-(4-fluoro-3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine and2-(4-methylpiperazin-1-yl)ethanamine yielded6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-benzo[d]imidazole.¹H NMR (DMSO-d6): δ 9.52 (d, J=1.3 Hz, 1H), 8.89-8.65 (m, 1H), 8.19 (dd,J=7.8, 1.6 Hz, 1H), 7.95 (s, 1H), 7.89-7.65 (m, 2H), 7.46-7.20 (m, 2H),7.11 (t, J=7.7 Hz, 1H), 6.95 (d, J=5.7 Hz, 1H), 4.55 (s, 2H), 2.82-2.75(m, 10H), 2.52 (s, 3H), 2.20 (s, 3H). MS (m/e): 430 (MH⁺).

Example 501-(3-Ethoxypropyl)-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole(Compound 39)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole, the reaction of2-(3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine and3-ethoxypropan-1-amine yielded1-(3-Ethoxypropyl)-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole. ¹HNMR (DMSO-d6): δ 9.55 (d, J=1.2 Hz, 1H), 8.97-8.67 (m, 1H), 8.32-8.13(m, 1H), 7.86 (s, 1H), 7.82-7.66 (m, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.25(s, 1H), 7.21-7.01 (m, 2H), 6.96 (d, J=6.4 Hz, 1H), 4.45 (t, J=6.7 Hz,2H), 3.43-3.10 (m, 4H), 2.19 (s, 3H), 2.00-1.78 (m, 2H), 0.95 (td,J=7.0, 1.1 Hz, 3H). MS (m/e): 372 (MH⁺).

Example 516-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-benzo[d]imidazole(Compound 40)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole,the reaction of2-(4-fluoro-3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine and2-(4-methylpiperazin-1-yl)ethanamine yielded6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-benzo[d]imidazole.¹H NMR (DMSO-d6): δ 9.42 (s, 1H), 8.79 (d, J=5.4 Hz, 1H), 8.74-7.84 (m,1H), 7.75 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.5 Hz, 1H), 7.07-6.63 (m, 2H),4.55 (s, 2H), 3.15 (s, 2H), 2.93-2.86 (m, 8H), 2.78 (s, 2H), 2.52 (s,3H), 2.09 (s, 3H). MS (m/e): 444 (MH⁺).

Example 523-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)propan-1-ol(Compound 41)

In like manner to the preparation of6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole,the reaction of2-(4-fluoro-3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine and3-aminopropan-1-ol yielded3-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)propan-1-ol.¹H NMR (DMSO-d6): δ 9.51 (s, 1H), 8.78 (dd, J=5.1, 1.5 Hz, 1H),8.37-8.13 (m, 1H), 7.87 (s, 1H), 7.82-7.69 (m, 2H), 7.35 (dd, J=8.5, 1.4Hz, 2H), 6.98 (dd, J=9.5, 5.7 Hz, 2H), 3.35 (t, J=5.7 Hz, 2H), 2.52 (s,2H), 2.10 (s, 3H), 1.95-1.62 (m, 2H). MS (m/e): 362 (MH⁺).

Example 531-(3-Ethoxypropyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-benzo[d]imidazole(Compound 42)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole,the reaction of2-(4-fluoro-3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine and3-ethoxypropan-1-amine yielded1-(3-ethoxypropyl)-6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-benzo[d]imidazole.¹H NMR (DMSO-d6): δ 9.55 (d, J=1.3 Hz, 1H), 8.83-8.65 (m, 1H), 8.10 (dd,J=7.8, 1.6 Hz, 1H), 7.87 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.72-7.58 (m,1H), 7.46-7.26 (m, 2H), 6.96 (t, J=7.2 Hz, 2H), 4.46 (t, J=6.5 Hz, 2H),3.32-3.25 (m, 4H), 2.11 (s, 3H), 2.02-1.74 (m, 2H), 0.96 (t, J=7.0, 3H).MS (m/e): 390 (MH⁺).

Example 54 1-Ethyl-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole(Compound 43)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole, the reaction of2-(3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine and ethanamineyielded 1-Ethyl-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole ¹H NMR(DMSO-d6): δ 9.53 (s, 1H), 8.77 (dd, J=5.0, 1.5 Hz, 1H), 8.13 (dd,J=7.8, 1.5 Hz, 1H), 7.92 (s, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.67 (dd,J=7.8, 5.0 Hz, 1H), 7.43-7.19 (m, 2H), 7.16-6.97 (m, 2H), 6.93 (d, J=6.6Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.20 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).MS (m/e): 314 (MH⁺).

Example 551-(Tetrahydro-2H-pyran-4-yl)-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole(Compound 44)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole, the reaction of2-(3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine andtetrahydro-2H-pyran-4-amine yielded1-(tetrahydro-2H-pyran-4-yl)-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole¹H NMR (DMSO-d6): δ 9.59 (d, J=1.3 Hz, 1H), 8.90-8.68 (m, 1H), 8.27-8.11(m, 1H), 7.96 (s, 1H), 7.89-7.63 (m, 2H), 7.75-7.61 (m, 1H), 7.38 (d,J=8.6 Hz, 1H), 7.30 (s, 1H), 7.19-6.98 (m, 2H), 6.92 (d, J=7.1 Hz, 1H),4.82 (s, 1H), 3.98 (m, 2H), 3.47 (m, 2H), 2.21 (s, 3H), 1.96 (bs, 4H).MS (m/e): 370 (MH⁺).

Example 561-(1-Methylpiperidin-4-yl)-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole(Compound 45)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole, the reaction of2-(3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine and1-methylpiperidin-4-amine yielded1-(1-Methylpiperidin-4-yl)-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole.¹H NMR (DMSO-d6): δ 9.43 (s, 1H), 8.78 (d, J=3.9 Hz, 1H), 8.15 (d, J=7.2Hz, 1H), 7.94 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.68 (dd, J=7.7, 5.0 Hz,1H), 7.43-7.19 (m, 2H), 7.08 (d, J=7.2 Hz, 2H), 6.93 (d, J=6.9 Hz, 1H),4.87 (s, 1H), 3.62 (m, 2H), 3.17 (m, 2H), 2.85 (s, 3H), 2.26 (s, 4H),2.20 (s, 3H). MS (m/e): 383 (MH⁺).

Example 571-Ethyl-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-benzo[d]imidazole(Compound 46)

In like manner to the preparation of6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole,the reaction of2-(4-fluoro-3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine andethanamine yielded1-Ethyl-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-benzo[d]imidazole.¹H NMR (DMSO-d6): δ 9.38 (s, 1H), 8.76 (d, J=5.4 Hz, 1H), 8.38 (d, J=7.8Hz, 1H), 7.99-7.67 (m, 2H), 7.74 (d, J=8.6 Hz, 1H), 7.34 (t, J=6.1 Hz,2H), 7.16-6.87 (m, 2H), 4.49-4.29 (m, 2H), 2.08 (s, 3H), 1.32 (t, J=7.2Hz, 3H). MS (m/e): 332 (MH⁺).

Example 585-(2-(3-Cyclopentylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(Compound 171)

5-(2-(3-cyclopentenylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine(130 mg) was hydrogenated with Pd/C (15 mg) in EtOH (15 mL) over aperiod of 10 h under balloon H₂ after degassing and back filling theflask with the hydrogen. The reaction mixture was filtered throughcelite and purified by preparative HPLC to provide5-(2-(3-cyclopentylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine as awhite solid. ¹H NMR (DMSO-d6): δ 8.84 (d, 1H, J=4.7 Hz), 8.41 (d, 1H,J=7.9 Hz), 8.16 (app s, 2H), 8.14 (app s, 1H), 7.89 (app t, 1H, J=7.5Hz), 7.23 (app s, 2H), 7.22-7.20 (m, 1H), 7.08 (s, 1H), 2.80 (q, 1H,J=8.2 Hz), 1.75-1.68 (m, 2H), 1.48-1.39 (m, 4H), 1.17-1.07 (m, 2H).LCMS: rt 5.13 min (A), purity 97%, MS (m/e) 341 (MH⁺).

Example 59 5-(2-(6-Methylpyridin-2-yl)pyridin-3-yl)-1H-indazole(Compound 116)

A vial with a piercable teflon cap containing a magnetic stir was wascharged with 5-[2-(4-fluoro-3-methylphenyl)pyridin-3-yl]-1H-indazole(0.2 g, 0.87 mmol), Pd₂(dba)₃ (30 mg, 0.03 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPHOS, 60 mg,0.13 mmol) under argon atmosphere. 6-Methyl-2-pyridylzinc bromide (0.5 Min THF, 4.0 mL, 2 mmol) was added to above reactants and degassed undervacuum. After three degas cycles, the reaction mixture was heated at 65°C. under argon. After 6 h, the reaction mixture was cooled to the roomtemperature and diluted with Rochelle salt (5 mL) and concentrated toremove the volatiles. The concentrated aqueous solution was diluted withEtOAc (30 mL) and separated the organic layer. Aqueous solution wasfurther extracted with EtOAc (30 mL). Combined organic layers washedwith aq. NaCl (10 mL), stirred over MgSO₄, and filtered through a pad ofFlorosil/celite. The filtrate was concentrated and purified bypreparative HPLC. The collected fractions were concentrated, dilutedwith water and neutralized with aq. NaHCO₃. The resultant solid formedwas collected by filtration and dried to provide5-(2-(6-Methylpyridin-2-yl)pyridin-3-yl)-1H-indazole (118 mg, 47%) as awhite solid. ¹H NMR (DMSO-d6): δ 13.01 (s, 1H), 8.63 (dd, 1H, J=0.8 and4.7 Hz), 7.99 (s, 1H), 7.89 (d, 1H, J=7.9 Hz), 7.57 (app d, 2H, J=8.5Hz), 7.51 (dd, 1H, J=4.9 and 7.6 Hz), 7.34 (d, 1H, J=8.8 Hz), 7.26 (d,1H, J=7.6 Hz), 7.07 (d, 1H, J=7.6 Hz), 6.97 (d, 1H, J=8.8 Hz), 2.15 (s,3H). LCMS: rt 2.13 min (B), purity 97%, MS (m/e) 287 (MH⁺).

Example 60 Methyl 2-Amino-5-bromo-3methylbenzoate

2-Amino-5-bromo-3-methylbenzoic acid (5.0 g, 21.7 mmol) in dry DMF (35mL) was stirred with Cs₂CO₃ (10.62 g, 32.6 mmol) at room temperature for1 h under nitrogen. Iodomethane (3.4 g, 1.5 mL, 23.95 mmol) in dry DMF(7 ml) was added dropwise to the above stirring reaction mixture over aperiod of 30 min and continued the reaction for 24 h. Reaction mixturewas diluted with water (200 mL) and stirred to observe hetergeneoussuspension. The purple solid was collected by filtration and dried toobtain methyl 2-amino-5-bromo-3-methylbenzoate (4.72 g, 89%). ¹H NMR(DMSO-d6): δ 7.67 (app d, 1H, J=2.1 Hz), 7.34 (s, 1H), 6.60 (s, 2H),3.78 (s, 3H), 2.09 (s, 3H). LCMS: rt 7.98 min (A), purity 99%, MS (m/e)245 (MH⁺).

Example 61 Methyl 5-bromo-1H-indazole-7-carboxylate

Acetic anhydride (4.5 g, 4.1 mL, 44 mmol) was added dropwise to thehomogenous solution of methyl 2-amino-5-bromo-3-methylbenzoate (4.72 g,19 mmol) in chloroform (55 mL) over a period of 20 min at roomtemperature and allowed to stir for 1h. Potassium acetate (5.7 g, 58mmol) and isoamyl nitrate (6.6 g, 7.6 mL, 57 mmol) were added at once tothe reaction mixture under nitrogen. The clear reaction mixture turnedto dark upon heating at 90° C. The reaction mixture was cooled to roomtemperature after overnight reflux, concentrated, diluted with water andstirred. The beige solid formed was collected by filtration and dried toobtain methyl 5-bromo-1H-indazole-7-carboxylate (2.1 g, 42%). ¹H NMR(DMSO-d6): δ 13.44 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H),3.95 (s, 3H). LCMS: rt 6.86 min (A), purity 99%, MS (m/e) 255 (MH⁺).

Example 62 Methyl 5-(2-chloropyridin-3-yl)-1H-indazole-7-carboxylate

Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,methyl 5-(2-chloropyridin-3-yl)-1H-indazole-7-carboxylate was preparedby heating the mixture of methyl 5-bromo-1H-indazole-7-carboxylate (2.0g, 7.8 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.9 g, 7.9mmol), Pd(PPh₃)₄ (540 mg, 0.46 mmol) and 2M aq. Na₂CO₃ (8 mL, 16 mmol)in 1,4-dioxane (70 mL). Methyl5-(2-chloropyridin-3-yl)-1H-indazole-7-carboxylate was isolated as awhite solid (920 mg, 41%) upon work-up and purification generalized inthe preparation of 5-(2-chloropyridin-3-yl)-1H-indazole. ¹H NMR(DMSO-d6): δ 13.41 (s, 1H), 8.45 (d, 1H, J=4.7 Hz), 8.31 (s, 1H), 8.21(s, 1H), 7.97 (d, 1H, J=7.3 Hz), 7.54 (dd, 1H, J=4.7 and 7.3 Hz), 3.99(s, 3H). LCMS: rt 6.41 min (A), purity 95%, MS (m/e) 288 (MH⁺).

Example 63 Methyl5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylate(Compound 190)

A single necked round bottom flask (100 mL) equipped with a magneticstirring bar was charged with methyl5-(2-chloropyridin-3-yl)-1H-indazole-7-carboxylate (0.88 g, 3.0 mmol),4-fluoro-3-methylphenyl boronic acid (0.56 g, 3.63 mmol), PdCl₂(PPh₃)₄(214 mg g, 1.0 mmol), 1,4-dioxane (75 mL) and 2M aq.Na₂CO₃ (4.2 mL, 8.4mmol mL) under argon atmosphere. The rubber septum was replaced withreflux condenser containing three-way stopcock. The system was thenevacuated three times and back filled with argon and externally heatedat 100° C. (oil bath) for 48h. The heterogeneous reaction mixture wasallowed to cool to room temperature and concentrated under vacuum toremove the volatiles by rotary evaporator. The crude concentrate flaskwas charged with chloroform (100 mL)/water (30 mL) and stirred. Organiclayer was separated and the aqueous layer further extracted withchloroform (75 mL). Combined organic layers were stirred overMgSO₄/Celite® for 20 min, suction filtered and filter cake washed withchloroform (30 mL). The filtrate collected was concentrated and purifiedby silica gel flash chromatography [Combiflash® Companion System® withRediSep® silica gel column (24 g), solvent eluent gradient 30-50%EtOAc/hexanes] to obtain methyl5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylate(420 mg, 39%) as a white solid. ¹H NMR (DMSO-d6): δ 13.1 (s, 1H), 8.62(dd, 1H, J=0.5 and 4.7 Hz), 8.04 (s, 1H), 7.83 (d, 1H, J=7.6 Hz), 7.66(s, 1H), 7.45-7.34 (app m, 3H), 7.02 (d, 1H, J=8.5 Hz), 6.96-6.85 (m,2H), 2.11 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −118.91. LCMS: rt 5.23 min (A),purity 93%, MS (m/e) 362 (MH⁺).

Example 645-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylicacid (Compound 195)

Methyl5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylate(300 mg, 0.55 mmol) was saponified by LiOH (0.12 g) in THF/H₂O (1:1, 8mL) for 2 days. The reaction mixture was concentrated to dryness,diluted with water (4 mL) and neutralized by the addition of aq. 2N HCl.The solid formed after the neutralization was filtered and suction driedto obtain the title compound as a white solid (220 mg). ¹H NMR(DMSO-d6): δ 13.15 (s, 1H), 8.67 (app dd, 1H, J=1.4 and 4.7 Hz), 8.17(s, 1H), 7.97-7.92 (m, 2H), 7.68 (d, 1H, J=1.7 Hz), 7.51 (dd, 1H, J=4.7and 7.6 Hz), 7.38 (d, 1H, 7.6 Hz), 6.93-6.90 (m, 2H), 2.12 (s, 3H). ¹⁹FNMR (DMSO-d6): δ −118.43 (s). LCMS: 97%, MS (m/e) 348 (MH⁺).

Example 65(5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanone(Compound 196)

A capped vial containing a stir-bar, was charged with5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylicacid (100 mg, 0.28 mmol), HBTU (140 mg, 0.36 mmol), morpholine (29 mg,0.03 mL, 0.34 mmol), NEt₃ (57 mg, 0.08 mL, 0.57 mmol) and acetonitrile(3 ml) successively and stirred the contents at room temperature. After12h, the reaction mixture was concentrated and diluted with EtOAc (15mL)/H₂O (5 mL). Organic layer was separated, washed with brine, driedover anhydrous Na₂SO₄, concentrated and purified by preparative HPLC.Product fractions were concentrated, diluted with water and neutralizedwith aq. Na₂CO₃ solution. The resulting white precipitate was filteredand dried to obtain(5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanone.¹H NMR (DMSO-d6): δ 13.27 (s, 1H), 8.66 (d, 1H, J=4.7 Hz), 8.17 (s, 1H),7.97-7.92 (m, 2H), 7.48 (dd, 1H, J=4.9 and 7.6 Hz), 7.33 (d, 1H, J=7.8Hz), 6.97-6.88 (m, 3H), 3.62-3.42 (m, 8H), 2.10 (s, 3H). ¹⁹F NMR(DMSO-d6): δ −118.69 (s). LCMS: rt 4.45 min (A), purity 97%, MS (m/e)417 (MH⁺).

Example 665-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamide(Compound 203)

5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamidewas prepared analogous to the preparation of5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanoneby the reaction of dimethyl amine (0.55 mL, 1.1 mmol, 2M in THF) with5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylicacid (100 mg, 0.28 mmol), HBTU (140 mg, 0.36 mmol), NEt₃ (57 mg, 0.08mL, 0.57 mmol) in acetonitrile (4 mL). Extractive work-up followed bypreparative HPLC purification and neutralization procedure as discussedpreviously provided desired5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamideas a white solid. ¹H NMR (DMSO-d6): δ 13.05 (s, 1H), 8.63 (dd, 1H, J=1.7and 4.7 Hz), 8.13 (s, 1H), 7.87 (dd, 1H, J=1.4 and 7.6 Hz), 7.81 (s,1H), 7.46 (dd, 1H, J=4.7 and 7.6 Hz), 7.32 (d, 1H, J=7.3 Hz), 7.02-6.98(m, 1H), 6.95-6.89 (app m. 2H), 2.93 (br s, 3H), 2.57 (br s, 3H), 2.09(s, 3H). ¹⁹F NMR (DMSO-d6): δ −118.91. LCMS: rt 4.63 min (A), purity97%, MS (m/e) 375 (MH⁺).

Example 67[5-(2-(4-Fluoro-3methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methyldihydrogen phosphate (Compound 172)

Step A:Di-tert-butyl[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methylphosphate

Freshly prepared chloromethyl di-tert-butylphosphate (93% pure, 0.5 g,1.93 mmol) dissolved in anhydrous DMF (1 mL) was added in one portion toa heterogeneous stirring mixture of5-[2-(4-fluoro-3-methylphenyl)pyridin-3-yl]-1H-indazole (0.5 g, 1.65mmol), cesium carbonate (0.64 g, 1.96 mmol) and DMF (3 mL) at roomtemperature under argon. The contents were heated at 50° C. and theprogress of the reaction monitored by LC/MS. After 24h, analysis of thereaction indicated the consumption of5-[2-(4-fluoro-3-methylphenyl)pyridin-3-yl]-1H-indazole (3%) with thegeneration of alkylated regio-isomeric product mixture ofdi-tert-butyl[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methylphosphate (N2, 28%) anddi-tert-butyl[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-1-yl]methylphosphate (N1, 60%). The reaction mixture was diluted with EtOAc (15mL), upon cooling to room temperature, stirred for 10 min and suctionfiltered. The filter cake was washed with EtOAc (15 mL) and discarded.Upon dilution of the filtrate with H₂O (20 mL)/t-BuOMe (30 mL), theaqueous layer was separated and the organic layer was washed with water(20 mL). The combined aqueous layers were re-extracted with a mixture oft-BuOMe/EtOAc (1/1, 30 mL). The combined organic layers were washed withsaturated aq. NaCl (30 mL), stirred over MgSO₄, filtered and resultingfiltrate evaporated under vacuum by rotary evaporator (water bathtemperature 26-28° C.). The crude (1.2 g) product was subjected topurification by flash chromatography [Combiflash® companion System® withRediSep® silica gel column 40 g (pretreated with 5% NEt₃ in 30%EtOAc/hexanes followed by wash with 30% EtOAc/hexanes), 30/50/60/90%EtOAC/hexanes eluting solvent gradient upon liquid loading on tocolumn]. Concentration of the fractions by rotary evaporator undervacuum provided the desired minor N2-regio-isomer,di-tert-butyl[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methylphosphate, as a viscous material (110 mg, 12%). ¹H NMR (DMSO-d6): δ 8.63(dd, 1H, J=1.7 and 4.7 Hz), 8.51 (d, 1H, J=0.9 Hz), 7.84 (dd, 1H, J=1.8and 8.0 Hz), 7.66 (d, 1H, J=0.9 Hz), 7.52 (d, 1H, J=8.8 Hz), 7.43 (dd,1H, J=4.5 and 7.6 Hz), 7.37 (d, 1H, J=2.0 and 7.6 Hz), 7.01-6.85 (m,3H), 6.10 (d, 2H, ³J_(PH)=11 Hz), 2.11 (s, 3H), 1.34 (s, 18 Hz). ³¹P NMR(DMSO-d6): δ −11.9. LCMS: 94%, MS (m/e) 526 (MH⁺).

Step B:[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methyldihydrogen phosphate

Di-tert-butyl[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methylphosphate (N2, 100 mg, 0.21 mmol) was dissolved in AcOH:H₂O (0.5 mL,4:1) and the clear homogenous solution heated at 60° C. After 1h,analysis of the reaction mixture LC/MS indicated the 97% consumption ofdi-tert-butyl[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methylphosphate leading to the desired product of[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methyldihydrogen phosphate (AUC 85%). At this stage heating was discontinuedand the reaction mixture was polish filtered by suction. Concentrationof the filtrate by rotary evaporator under vacuum (water bath temp26-28° C.) resulted in a thick viscous liquid which was diluted withacetone (7 mL). The white heterogenous suspension was stirred for 30 minand filtered. The filter cake was was washed with acetone (25 mL) andsuction dried for a period of 1h. The collected filter cake was furtherprocessed by drying under high vacuum over P₂O₅ for 24 h to provide[5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl]methyldihydrogen phosphate (63 mg, 71%). ¹H NMR (DMSO-d6): δ 8.64 (dd, 1H,J=0.5 and 4.7 Hz), 8.51 (s, 1H), 7.86 (d, 1H, J=7.6 Hz), 7.70 (s, 1H),7.50-7.41 (app m, 3H), 7.00-6.88 (m, 3H), 6.05 (d, 2H, ³J_(PH)=10 Hz),2.13 (s, 3H). ¹⁹F NMR (DMSO-d6): δ −118.60. ³¹P NMR (DMSO-d6): δ −2.63.LCMS: 97%, MS (m/e) 414 (MH⁺).

Example 68 (S)-2-Amino-3-(1H-indol-3-yl)propyl5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxylatetrifluoroacetic acid salt (Compound 179)

Step A:5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carbonylchloride

A single neck round bottom flask with a stir bar was charged with5-[2-(4-fluoro-3-methylphenyl)pyridin-3-yl]-1H-indazole (100 mg, 0.33mmol) and triphosgene (120 mg, 0.40 mmol). The reaction flask was cappedwith a septum with a nitrogen inlet subsequently. Dichloroethane (3 mL)was transferred and cooled the reaction flask to −70° C. i-Pr₂NEt (80mg, 0.11 mL, 0.60 mmol) was added dropwise to the above stirringreaction mixture over a period 5 min and allowed to stir for 15 minafter the competion of addition. The heterogenous suspension was allowedto warm to room temperature and heated at 90° C. Analysis of thereaction by LC/MS after 18h of heating indicated the formation of5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carbonylchloride [rt 6.55 min (A), AUC 59%] andbis(5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-1-yl)methanone[dimer, rt 6.16 min (A), 27%, MH+634]. The reaction mixture was cooledto room temperature and concentrated to dryness under vacuum by rotaryevaporation.

Step B:(S)-tert-Butyl-1-(5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxyloyloxy)-3-(1H-indol-3-yl)propan-2-ylcarbamate

N-(tert-Butoxycarbonyl)-L-tryptophanol (100 mg, 33 mmol), DMAP (40 mg,0.33 mmol) and CH₂Cl₂ (3 mL) were added sequentially to the aboveconcentrate containing5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carbonylchloride under nitrogen atmosphere at room temperature. The resultingpale yellow heterogenous stirring solution was treated with NEt₃ (0.5mL) over a period of 5 min. The resulting clear dark reaction mixturewas stirred for 30 min at room temperature. Analysis of the reactionmixture indicated the formation of desired product(S)-tert-butyl-1-(5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxyloyloxy)-3-(1H-indol-3-yl)propan-2-ylcarbamate[rt 7.10 min (A) AUC 56%) and dimer [rt 6.16 min (A), 20%, MH+634] withcomplete consumption of starting material. The reaction mixture wasconcentrated, diluted with EtOAc/H₂O (30 mL/10 mL) and separated theorganic layer. Aqueous layer was re-extracted with EtOAc (15 mL),stirred the combined organic layers over MgSO₄ and filtered. Filtratewas concentrated and used in the next step with no further purification.

Step C: (S)-2-Amino-3-(1H-indol-3-yl)propyl5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxylatetrifluoroacetic acid salt

The above concentrate (220 mg) containing(S)-tert-butyl-1-(5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxyloyloxy)-3-(1H-indol-3-yl)propan-2-ylcarbamatedissolved in MeOH (2 mL) was treated with 4.0 N HCl (3 mL) at roomtemperature and stirred the resulting homogenous solution. After 1 h,the reaction mixture was concentrated and purified by reverse phasepreparative HPLC containing TFA as a modifier in the mobile phase ofacetonitrile/water. The collected product fractions were allowed tofreeze by external cooling in dry ice/acetone. The frozen residue waslyophilized to provide (S)-2-amino-3-(1H-indol-3-yl)propyl5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxylate asan off-white solid (67 mg, 0.33%) as a TFA salt. ¹H NMR (DMSO-d6): δ11.04 (s, 1H), 8.68 (d, 1H, J=4.5 Hz), 8.49 (s, 1H), 8.17 (br s, 3H),7.99 (d, 1H, J=8.5 Hz), 7.90 (d, 1H, J=7.9 Hz), 7.80 (s, 1H), 7.60 (d,1H, J=7.9 Hz), 7.50 (dd, 1H, J=4.5 and 7.9 Hz), 7.36-7.31 (app m, 4H),7.09 (t, 1H, J=7.9 Hz), 6.98 (t, 1H, J=7.9 Hz), 6.92-6.86 (m, 3H), 4.62(app d, 1H, J=9.2 Hz), 4.52 (dd, 1H, J=J=7.0 and 9.4 Hz), 3.92-3.87 (brs, 1H), 3.12 (d, 2H, J=7.0 Hz), 2.13 (s, 3H). ¹⁹F NMR (DMSO-d6): δ−118.91 (s) and −74.47 (s). LCMS: rt 5.15 min (A), purity 94%, MS (m/e)520 (MH⁺)-TFA.

Example 69

Certain starting materials suitable for use in making the compoundsdescribed herein can be synthesized using the following referencesyntheses.

Synthesis, 16, 2551-2560 (2008).

Int'l Pat. App. Pub. no. 2009/027283

Int'l Pat. App. Pub. no. 2008/147822

Int'l Pat. App. Pub. no. 2008/078091

Example 70

Certain intermediates useful in making compounds of the disclosure(e.g., compounds 786-89, 795, 796 and 798-801) according to Schemes 12and 13 were prepared. General procedures are first provided. Particularstructures, compound names and synthetic data are provided thereafter.

General procedure for the preparation of 5- or6-(2-(aryl)pyridin-3-yl)-1H-indazol-3-amine: 2-Fluoro-4- or-5-(2-aryl)pyridin-3-yl)benzonitrile (75 mg) and EtOH (3 mL) weretransferred to a microwave tube containing a stir bar. Correspondinghydrazine was added to the stirring solution, sealed the tube with thecap and heated at 150° C. in the microwave for 35 min. The homogeneoussolution was concentrated and diluted with water. The resultant solidwas collected by filtration and suction dried overnight. Samples thatwere not solids were purified by preparative HPLC and lyophilized thepurified samples after the processing the samples to neutralization.

General procedure for 5 or6-(2-(phenyl)pyridin-3-yl)benzo[d]isoxazol-3-amine: t-BuOK (0.077 g,0.69 mmol) was added to a stirring solution of N-acetyl hydroxylamine(0.051 g, 0.69 mmol) in DMF (3 mL) at room temperature under argon in ascrew capped vial (20 mL). After 20 min, corresponding 2-fluoro-4 or5-(2-aryl)pyridin-3-yl)benzonitrile (1 eq) was added all at once to theheterogeneous suspension stirred for 30 min at rt. The pale yellowheterogeneous reaction mixture was stirred eventually at 60° C. After8h, the reaction mixture was diluted with water and solid formed wascollected by filtration. Thus collected solid was purified by eithercrystallization in EtOAc or preparative HPLC. Preparative HPLC purifiedproduct samples were neutralized with aq. NaHCO₃, subsequently filteredthe heterogeneous suspension and dried the collected solids.

2-Fluoro-4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)benzonitrile(intermediate for compounds 786, 787)

¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (dd, J=4.7, 1.7 Hz, 1H), 7.89 (dd,J=7.8, 1.7 Hz, 1H), 7.84 (dd, J=8.1, 7.0 Hz, 1H), 7.51 (dd, J=7.8, 4.8Hz, 1H), 7.46 (dd, J=10.5, 1.5 Hz, 1H), 7.33 (dd, J=7.4, 1.7 Hz, 2H),7.14 (dd, J=8.1, 1.6 Hz, 1H), 7.06-6.91 (m, 2H), 2.17 (d, J=1.7 Hz, 5H).¹⁹F NMR (282 MHz, DMSO-d₆) δ −108.32 (dd, J=10.5, 7.0 Hz), −118.03 (q,J=7.8 Hz).

4-(2-(3-Chlorophenyl)pyridin-3-yl)-2-fluorobenzonitrile (intermediatefor compounds 798)

¹H NMR (300 MHz, DMSO-d₆): δ 8.74 (dd, J=4.8, 1.7 Hz, 1H), 7.94 (dd,J=7.8, 1.7 Hz, 1H), 7.87 (t, J=7.5 Hz, 1H), 7.56 (dd, J=7.8, 4.8 Hz,1H), 7.49 (d, J=10.6 Hz, 1H), 7.47-7.41 (m, 1H), 7.41-7.34 (m, 1H), 7.28(t, J=7.8 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H). ¹⁹FNMR (282 MHz, DMSO-d₆) δ −108.32 (dd, J=10.5, 7.1 Hz).

2-Fluoro-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)benzonitrile(intermediate for compounds 795, 788, 789)

¹H NMR (300 MHz, DMSO-d₆): δ 8.68 (dd, J=4.7, 1.7 Hz, 1H), 7.98 (s, 1H),7.94-7.82 (m, 2H), 7.53-7.38 (m, 3H), 7.32 (d, J=7.5 Hz, 1H), 7.00 (dd,J=8.9, 3.1 Hz, 1H), 2.17 (d, J=1.5 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆):δ −110.59 (q, J=6.9 Hz), −118.29.

5-(2-(3-Chlorophenyl)pyridin-3-yl)-2-fluorobenzonitrile (intermediatefor compound 799)

¹H NMR (300 MHz, DMSO-d₆): δ 8.71 (dd, J=4.8, 1.6 Hz, 1H), 7.92 (dd,J=7.8, 1.7 Hz, 1H), 7.90-7.86 (m, 1H), 7.58-7.44 (m, 3H), 7.44-7.33 (m,2H), 7.27 (t, J=7.8 Hz, 1H), 7.16-7.04 (m, 1H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −110.39 (dt, J=9.1, 5.9 Hz).

4-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-2-fluorobenzonitrile(intermediate for compound 800)

¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (dd, J=4.7, 1.6 Hz, 1H), 7.92 (dd,J=7.8, 1.7 Hz, 1H), 7.87 (dd, J=8.0, 7.0 Hz, 1H), 7.63-7.47 (m, 3H),7.27 (t, J=7.8 Hz, 1H), 7.18 (dd, J=8.0, 1.5 Hz, 1H), 7.16-7.09 (m, 1H).¹⁹F NMR (282 MHz, DMSO-d₆) δ −108.18 (dd, J=10.5, 7.0 Hz), −116.79 (td,J=8.6, 4.9 Hz).

5-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-2-fluorobenzonitrile(intermediate for compound 796, 801)

¹H NMR (300 MHz, DMSO-d₆): δ 8.71 (d, J=1.6 Hz, 1H), 7.92 (t, J=1.7 Hz,1H), 7.90 (d, J=1.7 Hz, 1H), 7.62-7.41 (m, 4H), 7.37-7.24 (m, 1H), 7.14(ddd, J=8.6, 4.8, 2.2 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −110.28(dt, J=8.9, 5.9 Hz), −117.04 (ddd, J=9.3, 7.3, 4.7 Hz).

Example 73

Compound 291 was prepared according to the reaction sequence shown inScheme 22. The starting amine,2′-(3-chloro-4-fluorophenyl)-[3,3′-bipyridin]-6-amine, was prepared fromN-(2′43-chloro-4-fluorophenyl)-[3,3′-bipyridin]-6-yl)acetamide (¹H NMR(300 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.67 (dd, J=4.7, 1.7 Hz, 1H), 8.08(dd, J=2.5, 0.8 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.90 (dd, J=7.8, 1.7Hz, 1H), 7.60 (dd, J=8.6, 2.5 Hz, 1H), 7.55 (dd, J=7.4, 4.4 Hz, 1H),7.51 (dd, J=7.4, 4.4 Hz, 1H), 7.31 (t, J=8.6 Hz, 1H), 7.18 (ddd, J=8.6,4.8, 2.2 Hz, 1H), 2.07 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −117.24(td, J=8.3, 4.8 Hz)) via the following procedure:N-(2′-chloro-[3,3′-bipyridin]-6-yl)acetamide (2.5 g) and freshlyprepared MeOH.HCl (10 mL) in 1,4-dioxane (35 mL) were heated to stir at90° C. for 4h. The reaction mixture was concentrated and the cruderesidue was diluted with water (25 mL). The clear solution wasneutralized with aq. NaHCO₃ and extracted into CH₂Cl₂ (2×125 mL).Work-up and drying of the pale yellow residue under high vacuum for 2days provided 2′43-chloro-4-fluorophenyl)-[3,3′-bipyridin]-6-amine as apale yellow solid. (1.9 g, purity: 96%). ¹H NMR (300 MHz, DMSO-d₆) δ8.59 (dd, J=4.8, 1.7 Hz, 1H), 7.79 (dd, J=7.8, 1.7 Hz, 1H), 7.73 (d,J=2.5 Hz, 1H), 7.53 (dd, J=7.3, 2.1 Hz, 1H), 7.44 (dd, J=7.8, 4.7 Hz,1H), 7.33 (t, J=8.6 Hz, 1H), 7.24 (ddd, J=8.6, 4.9, 2.1 Hz, 1H), 7.12(dd, J=8.5, 2.5 Hz, 1H), 6.35 (dd, J=8.6, 0.8 Hz, 1H), 6.04 (s, 2H).

Example 74

Compounds in which the Z group is an amine-substituted pyrimidine (e.g.,Compounds 903-909 and 919) can be prepared via the reactions outlined inScheme 29, described in more detail below:

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-2-methoxypyrimidine(Compound 207)

¹H NMR (300 MHz, DMSO-d₆): δ 8.74 (dd, J=4.8, 1.7 Hz, 1H), 8.48 (d,J=5.1 Hz, 1H), 8.08 (dd, J=7.8, 1.7 Hz, 1H), 7.54 (dd, J=7.8, 4.8 Hz,1H), 7.34 (dd, J=7.6, 2.1 Hz, 0H), 7.11-6.98 (m, 2H), 6.90 (d, J=5.1 Hz,1H), 3.77 (s, 3H), 2.18 (app d, J=2.1 Hz, 2H). ¹⁹F NMR (282 MHz,DMSO-d₆): δ −118.09 (q, J=8.0, 7.5 Hz). LCMS: rt 5.04 min (B), purity99%, MS (m/e) 296 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2(1H)-one

Aqueous HCl (2N, 20 mL) was added to the stirring solution of4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2-methoxypyrimidine (1.3 g)in MeOH (10 mL) and heated at 90° C. for 12h. The reaction mixture wasconcentrated by rotary evaporator under reduced pressure and neutralizedthe resultant pale yellow viscous material with aq. NaHCO₃ solution. Theslurry thus formed upon neutralization was stirred at room temperaturefor 20 min. The solid was collected by filtration, washed with water,suction dried. After 6h, the solid was further dried over P₂O₅ underhigh vacuum to provide6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2(1H)-one as awhite solid (0.87 g). ¹H NMR (300 MHz, DMSO-d₆): δ 11.92 (s, 1H), 8.74(dd, J=4.8, 1.7 Hz, 1H), 7.98 (dd, J=7.8, 1.7 Hz, 1H), 7.80 (app d,J=6.0 Hz, 1H), 7.51 (dd, J=7.8, 4.8 Hz, 1H), 7.43 (dd, J=7.7, 2.1 Hz,1H), 7.24-7.02 (m, 2H), 5.96 (d, J=6.0 Hz, 1H), 2.22 (app s, 3H). ¹⁹FNMR (282 MHz, DMSO-d₆) δ −117.63.

2-Chloro-4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidine

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2(1H)-one (0.83 g)and POCl₃ (3 mL) were heated at 130° C. under nitrogen. The reactionmixture was cooled to room temperature upon completion of the reaction(2h). The volatiles were removed and quenched the concentrate with ice.The semi-heterogeneous slurry was neutralized with aq. NaHCO₃ solutionwhile stirring, warmed to room temperature and diluted with EtOAc (200mL). The organic layer was separated, stirred over MgSO₄, filtered,concentrated and purified by flash chromatography (Combiflash® CompanionSystem® with RediSep® silica gel column 12 g and 10-50% EtOAc/Hexanes aseluting solvent) to obtain2-chloro-4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidine as aclear viscous liquid.

General procedure for4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-arylpyrimidin-2-amine:2-chloro-4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidine (1 eq),Ar—NH₂ (1.3 eq), EtOH (3 mL) and catalytic amount of 4.0 M HCl (0.02 mL)were added successively to a microwave tube containing a stir bar. Thecontents were stirred for 2 min and heated in the microwave at 160° C.for 50 min. The reaction mixture was concentrated and purified bypreparative HPLC. The concentrated product fractions thus obtained assalts were neutralized with aq. NaHCO₃ solution and extracted intoEtOAc. Organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The concentrate was dissolved in acetonitrile/water (1:1)and lyophilized upon freezing the samples to obtain the desiredcompounds as solids.

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2-amine (Compound919) was prepared as follows: A screw capped vial was charged with2-chloro-4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidine (125 mg),28% aq. Ammonia (3 mL), 1,4-dioxane (3 mL) and a stir bar. The vial wascapped tightly, heated and stirred at 60° C. for 12h. The heterogeneoussolution was cooled to room temperature, diluted with water, filtered.The solid (90 mg) was suspended in 50% EtOAc/hexanes, stirred and heatedat 80° C. for 30 min. Upon cooling to room temperature, the suspensionwas filtered and the solid was suction dried to provide4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2-amine as a whitesolid (73 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 8.69 (dd, J=4.7, 1.7 Hz,1H), 8.07 (d, J=5.0 Hz, 1H), 7.93 (dd, J=7.8, 1.7 Hz, 1H), 7.47 (dd,J=7.8, 4.8 Hz, 1H), 7.38 (dd, J=7.4, 1.6 Hz, 1H), 7.18-6.95 (m, 2H),6.70 (s, 2H), 6.20 (d, J=5.0 Hz, 1H), 2.19 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆): δ −118.16 (q, J=7.7 Hz). LCMS: rt 4.40 min (A), purity 99%, MS(m/e) 281 MH⁺.

Example 75

N-alkyl indazole compounds (e.g., Compounds 750 and 751) can be preparedfrom the corresponding indazoles via the reaction outlined in Scheme 29,described in more detail below:

2-(5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-1-yl)acetamide(Compound 750) and2-(5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl)acetamide(Compound 751). 5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole(0.2 g, 0.66 mmol), 2-bromoacetamide (0.1 g, 0.72 mmol) and Cs₂CO₃ (0.25g, 0.79 mmol) in dry DMF (2.5 mL) was stirred under argon in a screwcapped vial at room temperature. The reaction mixture was diluted withwater after 2 days and the resultant solid was collected by filtration.Individual alkylated indazole regio-isomers (2:1 ratio Cpd 750:751) wereisolated from the crude solid by flash column chromatographicpurification (Combiflash® Companion System® with RediSep® silica gelcolumn 12 g and 0-1.5% MeOH/EtOAc as an eluting solvent).

Example 76

6- or 7-(2-(Aryl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylic acidsor esters via the reaction outlined in Scheme 19.

For example, ethyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(Compound 256) and6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylicacid (Compound 257) can be prepared using the intermediates andpreparations described below:

2′-(4-Fluoro-3-methylphenyl)-[3,3′-bipyridine]-6-carbonitrile. ¹H NMR(300 MHz, DMSO-d₆): δ 8.73 (dd, J=4.7, 1.3 Hz, 1H), 8.52 (d, J=1.9 Hz,1H), 8.01 (d, J=8.0 Hz, 1H), 7.96 (dd, J=7.8, 1.3 Hz, 1H), 7.87 (dd,J=8.0, 2.1 Hz, 1H), 7.54 (dd, J=7.8, 4.8 Hz, 1H), 7.31 (d, J=7.7 Hz,1H), 7.06-6.93 (m, 2H), 2.16 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−117.91 (q, J=7.6, 6.9 Hz).

(2′-(4-Fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine.2′44-Fluoro-3-methylphenyl)-[3,3′-bipyridine]-6-carbonitrile (2.2 g),Pd/C (0.4g) and conc. HCl (3 mL) in EtOH (100 mL) was hydrogenated in apar shaker at 40 psi overnight. The reaction mixture was filteredthrough Celite® and concentrated. The concentrate was treated withCH₂Cl₂ (120 mL) and sat. aq. NaHCO₃ (25 mL). Organic layer was separatedand the aqueous layer was re-extracted with CH₂Cl₂ (2×50 ml). Combinedorganic layers were stirred over anhydrous Na₂SO₄ for 30 min, filtered,concentrated and dried under high vacuum to obtain thick viscous liquidof (2′-(4-Fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine (2.1g, purity 97%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.66 (dd, J=4.7, 1.6 Hz,1H), 8.26 (s, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.54 (dd, J=8.0, 2.2 Hz, 1H),7.48 (dd, J=7.7, 4.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz,1H), 6.97 (dd, J=6.9, 1.5 Hz, 2H), 3.78 (s, 2H), 2.58 (br s, 2H), 2.16(s, 3H).

Ethyl2-4(2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)amino)-2-oxoacetate.To a stirring solution of(2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine (2.0g)in CH₂Cl₂ (30 mL) under nitrogen atmosphere, i-Pr₂NEt (2.6 mL) was addedand stirred for 10 min at room temperature. Ethyl 2-chloro-2-oxoacetate(1.1 mL) as neat was added dropwise for 10 min. After 1 h, the reactionmixture was concentrated, partitioned between CH₂Cl₂ (75 mL)/aq. NaCl(20 mL) and the organic layer was separated. Usual workup andpurification by chromatography (Combiflash® Companion System® withRediSep® silica gel column 40 g and 50-100% EtOAc/hexanes as an elutant)provided 1.4 g of ethyl2442′44-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)amino)-2-oxoacetateas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.41 (t, J=6.2 Hz,1H), 8.67 (dd, J=4.7, 1.7 Hz, 1H), 8.30 (dd, J=2.4, 0.9 Hz, 1H), 7.87(dd, J=7.8, 1.7 Hz, 1H), 7.56 (dd, J=8.1, 2.3 Hz, 1H), 7.49 (dd, J=7.8,4.8 Hz, 1H), 7.29-7.22 (m, 2H), 6.98 (dd, J=7.7, 1.1 Hz, 2H), 4.42 (d,J=6.1 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 2.21-2.09 (m, 3H), 1.26 (t, J=7.1Hz, 3H).

Ethyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(Compound 256). Ethyl2-4(2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)amino)-2-oxoacetate(1.4g) and POCl₃ (15 mL) were stirred and heated at 105° C. under argonballoon. The reaction mixture was cooled to room temperature, added anadditional amount of POCl₃ (10 mL) was added to the reaction mixture andheated at 90° C. for 2 days. The reaction mixture was cooled to roomtemperature and concentrated. Subsequently, ice/water solution was addedto the crude residue followed by CH₂Cl₂ and aq. NaHCO₃. Upon allowingthe contents warm to room temperature, organic layer was separated,stirred over Na₂SO₄, filtered and concentrated. Purification of thecrude residue by flash column chromatography (Combiflash® companionSystem® with RediSep® silica gel column 40 g and 0-50-75% EtOAC/hexanesas an eluting solvent) provided 315 mg of Ethyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylateas a white pale yellow solid.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylicacid (Compound 257). Ethyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(2.1 g) and LiOH.H₂O (400 mg) were stirred in THF/H₂O (1:1, 60 mL) at70° C. for 2h. The reaction mixture was concentrated to dryness anddiluted the pale yellow solid with water. The resultingsemi-heterogeneous suspension was cooled in ice-bath, stirred andneutralized with aq. 3N HCl to pH 6. The solid aggregate was collectedby filtration on Buchner funnel, washed with water and suction dried.Further processing the sample by drying over P₂O₅ in a vacuum desiccatorprovided the desired6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylicacid (1.5 g, purity: 97%) as a pale yellow solid.

Similarly, ethyl7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(Compound 255) and7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylicacid (Compound 258) can be prepared using the intermediates describedbelow:

2-(4-Fluoro-3-methylphenyl)-[3,4′-bipyridine]-2′-carbonitrile. ¹H NMR(300 MHz, DMSO-d₆): δ 8.74 (dd, J=4.8, 1.6 Hz, 1H), 8.63 (dd, J=5.1, 0.7Hz, 1H), 8.02-7.90 (m, 2H), 7.54 (dd, J=7.8, 4.8 Hz, 1H), 7.45 (dd,J=5.1, 1.7 Hz, 1H), 7.33 (d, J=6.4 Hz, 1H), 7.09-6.94 (m, 2H), 2.17 (s,3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.73 (q, J=7.7, 7.2 Hz).

(2-(4-Fluoro-3-methylphenyl)-[3,4′-bipyridin]-2′-yl)methanamine. ¹H NMR(300 MHz, DMSO-d₆): δ 8.69 (dd, J=4.7, 1.6 Hz, 1H), 8.34 (d, J=3.8 Hz,1H), 7.87 (d, J=1.6 Hz, 1H), 7.50 (dd, J=7.8, 4.7 Hz, 1H), 7.42-7.22 (m,2H), 6.99-6.90 (m, 3H)), 3.76 (s, 2H), 3.28 (br s, 2H), 2.16 (s, 3H).¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.23 (d, J=7.8 Hz). 3HCL: ¹⁹F NMR (282MHz, DMSO-d₆): δ 11.13 (s, 2H), 8.87 (d, J=4.9 Hz, 3H), 8.54 (d, J=5.3Hz, 1H), 8.30 (d, J=7.6 Hz, 1H), 8.06-7.80 (m, 2H), 7.43 (d, J=6.9 Hz,1H), 7.31-6.88 (m, 3H), 4.23 (d, J=5.2 Hz, 3H), 2.18 (s, 3H).

Ethyl2-(((2-(4-fluoro-3-methylphenyl)-[3,4′-bipyridin]-2′-yl)methyl)amino)-2-oxoacetate.¹H NMR (300 MHz, DMSO-d₆): δ 9.29 (t, J=6.0 Hz, 1H), 8.69 (d, J=4.7 Hz,1H), 8.42 (d, J=5.0 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.50 (dd, J=8.0,4.5 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J=5.0 Hz,1H), 7.01-6.88 (m, 2H), 4.37 (d, J=6.1 Hz, 2H), 4.23 (q, J=6.9 Hz, 2H),2.13 (s, 3H), 1.27 (t, J=6.9 Hz, 3H).

Example 75

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine(Compound 269) can be prepared via the reactions shown in the first twosteps of Scheme 20:(2′-(4-Fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine (2.18 g)and formic acid (15 mL) were stirred and heated under nitrogenatmosphere at 100° C. After 72h, the reaction mixture was concentratedand partitioned between CH₂Cl₂/aq. NaHCO₃. Usual work-up andpurification by flash column chromatography (Combiflash® CompanionSystem® with RediSep® silica gel column 40 g and 50-100% EtOAC/hexanesas elutant) provided 630 mg ofN-((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)formamideas an off white solid.N-((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)formamide(630 mg) and POCl₃ (3 mL) were stirred and heated in benzene (20 mL)overnight at 75° C. The reaction mixture was cooled to room temperatureand concentrated. Subsequently, ice/water solution was added to thecrude residue followed by CH₂Cl₂ and aq. NaHCO₃. Upon allowing thesolution warm to room temperature, organic layer was separated, stirredover Na₂SO₄, filtered and concentrated. Purification of the cruderesidue by flash column chromatography (Combiflash® companion System®with RediSep® silica gel column 40 g and 2-8% MeOH/CH₂Cl₂ as an elutingsolvent) provided 320 mg of6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine as anoff-white solid.

Example 76

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridin-3-amine(Compound 285) can be prepared via the reactions shown in Scheme 30,below:

Cyanogen bromide (62 mg) in dry acetonitrile (1 mL) was added to a screwcapped vial containing a stirring solution of(2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine.xHCl(120 mg), i-Pr₂NEt (0.2 mL) and anhydrous toluene. After 4h, thereaction mixture was concentrated and purified by reverse phasepreparative HPLC conditions provided6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridin-3-amine(28 mg).

Example 77

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine(Compound 291) can be prepared via the reactions shown in Scheme 22:Ethoxycarbonyl isothiocyanate (66 mg) added to a screw capped vialcontaining 2′-(3-Chloro-4-fluorophenyl)-[3,3′-bipyridin]-6-amine (150mg) and 1,4-dioxane (1.5 mL). After 6h, the reaction mixture wasconcentrated in the same vial to dryness and the residue was transferredto a microwave vial by dissolving in MeOH (1 mL) and EtOH (1 mL).Subsequently, hydroxylamine hydrochloride (35 mg) was added, capped thevial, introduced i-Pr₂NEt (87 μL) and heated at 150° C. Reaction mixturewas concentrated after overnight and diluted with water. The solid wascollected by filtration and purified by reverse phase preparative HPLCconditions.

Example 78

Pyrido[3,2-d]pyrimidine compounds can be prepared via the reactionsshown in Scheme 31, below:

6-Chloro-4-methoxypyrido[3,2-d]pyrimidine4,6-Dichloropyrido[3,2-d]pyrimidine (prepared from Int'l Pat. App. Pubs.nos. 2005058913, 2011131741 and 201009469) (2.5 g, 12.4 mmol) and NaHCO₃(3.1 g, 31 mmol) in MeOH (20 mL) were heated at 70° C. for 12h undernitrogen atmosphere. The reaction mixture was filtered and concentratedthe filtrate. The crude concentrate was diluted with water and filtered.The suction dried solid was stirred in EtOAc (20 mL) and filtered toobtain 6-chloro-4-methoxypyrido[3,2-d]pyrimidine (1.8 g) as an off-whitesolid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.88 (s, 1H), 8.37 (d, J=8.8 Hz,1H), 8.00 (d, J=8.8 Hz, 1H), 4.14 (s, 3H).

6-(2-Chloropyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine. A reactionflask was charged 6-chloro-4-methoxypyrido[3,2-d]pyrimidine (3.5 g, 17.8mmol), 2-chloro-3-pyridineboronic acid pinacol ester (4.35 g, 18.2mmol), Na₂CO₃ (4.0 g, 38.2 mmol) and 1,4-dioxane (100 mL) and a stirbar. The contents were degassed by vacuum and back filled with argonthree times while stirring. Subsequently, Pd(PPh₃)₃ (0.87 g, 0.75 mmol)was added to the reaction contents, repeated degassing cycles and heatedunder argon at 98° C. The heating was stopped after overnight, theyellow hot heterogeneous reaction mixture was suction filtered on aBuchner funnel and washed the cake with additional amount of dioxane (30mL). The pale yellow clear filtrate solution was passed through a pad ofCelite® and concentrated the filtrate. The crude pale yellow solidresidue was partitioned between CH₂Cl₂ (150 mL)/water (50 mL). Theorganic layer was separated, dried over MgSO₄, filtered andconcentrated. The crude concentrate was stirred in EtOAc (30 mL) andsuction filtered. The filter cake was washed further with EtOAc (10 mL)and dried to obtain 1.6 g of6-(2-chloropyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine (purity: 95%)as a white solid. The filtrate was concentrated and purified theconcentrate by flash column chromatography (Combiflash® CompanionSystem® with RediSep® silica gel column 40 g, 0-30-60% EtOAC/hexaneseluting solvent gradient) to obtain additional 0.65 g of titledcompound. ¹H NMR (300 MHz, DMSO-d₆): δ 8.92 (s, 1H), 8.57 (dd, J=4.8,2.0 Hz, 1H), 8.45 (d, J=8.7 Hz, 1H), 8.28 (d, J=8.7 Hz, 1H), 8.13 (dd,J=7.6, 2.0 Hz, 1H), 7.63 (dd, J=7.6, 4.8 Hz, 1H), 4.16 (s, 3H).

6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine(Compound 968).6-(2-chloropyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine (2.0 g, 7.3mmol), 3-chloro-4-fluoro-phenylboronic acid (2.5 g, 14.3 mmol), KF (2.5g, 43.0 mmol) and 1,4-dioxane (75 mL) and stir bar were added to areaction flask. The contents were degassed by vacuum and back filledwith argon three times while stirring. Subsequently, commerciallyavailable catalyst Pd₂(dba)₃.t-Bu₃P.HBF₄ (1:2) (1 g, 0.67 mmol) wasadded to the reaction contents, repeated degassing cycles and heated at90° C. under argon. Colorimetric changes were observed after theintroduction of catalyst and as the reaction progressed from pale pinkto yellow to off-green slurries. After 6h, the reaction stirring wasstopped, filtered the hot slurry and washed the cake with additionalamount of dioxane (30 mL). The pale yellow clear filtrate solution waspassed through a pad of Celite® and concentrated the filtrate. The crudesolid residue was partitioned between CH₂Cl₂ (150 mL)/water (50 mL). Theorganic layer was separated, dried over MgSO₄, filtered andconcentrated. The crude concentrate was stirred in 60% EtOAc/hexanes (30mL), suction filtered and dried the solid to obtain 1.6 g of (purity:95%)6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidineas an off-white solid. The filtrate was concentrated and purified theconcentrate by flash column chromatography (Combiflash® CompanionSystem® with RediSep® silica gel column 40 g, 0-30-60% EtOAC/hexaneseluting solvent gradient) to obtain additional 0.65 of titled compound.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4(3H)-one (Compound 960). Conc. HCl (0.2 ml) was added to a stirringheterogeneous slurry of6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine(2.2 g) in EtOH (25 mL) at room temperature and heated the slurrygradually to 60° C. The pale yellow heterogeneous slurry transformed tohomogeneous solution in 15 min and turned to heterogeneous slurry backagain after 2h of heating. Heating and stirring was continued for 4h andcooled the reaction mixture to room temperature. The solid was collectedby filtration and concentrated the filtrate. The solid was neutralizedwith aq. NaHCO₃, filtered and dried to obtain title compound as a whitesolid (1.3 g).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine(Compound 964).6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4(3H)-one (100 mg, 0.28 mmol), phosphonitrilic chloride (100 mg, 0.28mmol) and as stir bar were transferred to a vial, capped and placedunder nitrogen atmosphere. Dry acetonitrile (3 mL) was transferred andallowed the contents to stir at room temperature. i-Pr₂NEt was added for2 min to the heterogeneous slurry. Upon stirring the red homogeneousslurry for 2h, nitrogen balloon was replaced with NH₃ balloon andstirred. After stirring the contents for 6h, the reaction mixture wasconcentrated and the crude residue was partitioned betweenchloroform/water. Organic layer was removed and re-extracted the aqueouslayer with chloroform. Usual workup and purification by preparative HPLCprovided6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine(16 mg) as a white solid.

Example 79

6,7-Diaryl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-ones (e.g., Compounds 292,293, 294) and6,7-diaryl-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazines (e.g.,Compounds 295, 296, 300) can be prepared from6,7-dibromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Int'l Pat. App.Publication no. 2011/077098) by adopting analogous Suzuki-Miyaurareaction conditions from previous examples, as shown in Scheme 23.Particular intermediates and reactions are described below.

7-Bromo-6-(4-fluoro-3-methylphenyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one.¹H NMR (300 MHz, DMSO-d₆) δ 10.97 (s, 1H), 7.56-7.26 (m, 3H), 7.19 (dd,J=9.8, 8.4 Hz, 1H), 4.83 (s, 2H), 2.26 (d, J=2.0 Hz, 3H). ¹⁹F NMR (282MHz, DMSO-d₆) δ −117.58 (ddt, J=8.5, 6.0, 3.0 Hz).

7-Bromo-6-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.¹H NMR (300 MHz, DMSO-d₆): δ 7.84 (s, 1H), 7.59-7.34 (m, 2H), 7.20 (dd,J=9.8, 8.5 Hz, 1H), 4.90 (s, 2H), 3.27 (s, 3H), 2.27 (d, J=1.8 Hz, 3H).¹⁹F NMR (282 MHz, DMSO-d₆) δ −117.43 (m).

7-Bromo-6-(4-fluoro-3-methylphenyl)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine.To the stirring solution of7-bromo-6-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one(595 mg) and THF (15 mL) under argon was added BH₃.THF (5.1 mL, 1Nsolution in THF) dropwise for 20 min. After 12h, the reaction mixturewas cooled in ice-bath and transferred 1N aq. HCl (16 mL). Subsequently,cooling bath was removed and heated at 80° C. for 1 h. The reactionmixture was concentrated, basified with aq. NaHCO₃ solution andextracted with EtOAc (2×125 mL). Workup of the combined organic layersfollowed by flash column chromatographic purification (Combiflash®Companion System® with RediSep® silica gel column 24 g and 30-50%EtOAc/hexanes eluting solvent) provided 450 mg of7-bromo-6-(4-fluoro-3-methylphenyl)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazineas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.45-7.32 (m, 2H),7.21 (s, 1H), 7.13 (dd, J=9.8, 8.5 Hz, 1H), 4.59-4.21 (m, 2H), 3.47-3.25(m, 2H), 2.88 (s, 3H), 2.25 (d, J=1.9 Hz, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −118.92 (m).

Example 80

Free amino-substituted amide compounds (e.g., Compounds 514, 663, 679)can be prepared according to Scheme 32, below. General syntheticprocedures are also provided.

Step A: A single necked pear shaped round bottom flask containing a stirbar and acid ArCOOH (100 mg, 1 eq) is stoppered with a rubber septum andnitrogen is introduced. Methylene chloride (4 mL) is added and stirredfor 5 min. Oxalyl chloride is added all at once followed by catalyticDMF (0.05 mL from stock solution of 0.05 mL of dry DMF dissolved in 4 mLof dry DMF) at room temp. The heterogeneous reaction solution turns toclear solution upon addition of DMF which eventually progresses to aheterogeneous slurry. After 3h, reaction mixture is concentrated byrotary evaporator under nitrogen atmosphere to dryness to form acidchloride ArCOCl.

Step B: DMAP (5 mol %) and the desired N-Boc-diamine (Boc-R—NH₂) (1.2eq) are weighed into the flask containing the acid chloride (as asemi-solid) with the stir bar. The flask is stoppered with a rubberseptum and nitrogen is introduced. Methylene chloride (7 mL) istransferred and allowed to stir with the reaction contents. Afterstirring the contents for 10 min, i-Pr₂NEt is added drop-wise over aperiod of 5 min. The pale yellow homogeneous reaction mixture isconcentrated after 1 h to yield crude amide ArCONHR-Boc.

Step C: The crude residue from step B is stirred with 4.0 N HCl indioxane (3 mL) and MeOH (3 mL) at room temperature for 1 h. At the endof the reaction, the reaction mixture is concentrated and purified bypreparative reverse HPLC. The purified concentrate (obtained as eitherTFA salt or formic acid salt/solvate) is neutralized with aq. NaHCO₃solution and extracted with EtOAc. The organic layer is stirred withNa₂SO₄, polish filtered and concentrated. The concentrate is dissolvedin acetonitrile/water and lyophilized to obtain the desired productArCONHR.

Example 81

The following additional compounds were prepared substantially asdescribed herein. In certain cases, synthetic preparations are providedbelow.

5-(2-(3-Cyclopropyl-4-fluorophenyl)pyridin-3-yl)-1H-indazole (Compound211). LCMS: rt 5.21 min (A), MS (m/e) 330 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.78 (dd, J=5.4, 1.5 Hz, 1H), 8.55 (dd, J=7.8, 1.5 Hz, 1H), 8.08 (m,1H), 7.98 (dd, J=7.8, 5.4 Hz, 1H), 7.75 (m, 1H), 7.50 (m, 1H), 7.28 (m,1H), 7.14-7.05 (m, 2H), 6.88 (dd, J=6.9, 2.1 Hz, 1H), 1.96 (m, 1H), 0.82(m, 2H), 0.24 (m, 2H);

N-Cyclopropyl-6-(4-fluoro-3-methylphenyl)-5-(1H-indazol-5-yl)pyridin-3-amine(Compound 212). LCMS: rt 5.65 min (A), MS (m/e) 359 MH⁺.

1-(6-(3-Cyclopropylphenyl)-5-(1H-indazol-5-yl)pyridin-3-yl)-3-isopropylurea(Compound 213). LCMS: rt 5.48 min (A), MS (m/e) 412 MH⁺.

1-(5-(1H-Indazol-5-yl)-6-(m-tolyl)pyridin-3-yl)-3-isopropylurea(Compound 214). LCMS: rt 5.15 min (A), MS (m/e) 386 MH⁺.

5-(2-(4-Fluoro-3-methylphenyl)-5-(3-isopropylureido)pyridin-3-yl)-N-isopropyl-1H-indazole-1-carboxamide(Compound 215). LCMS: rt 6.56 min (A), MS (m/e) 489 MH⁺.

2-(2-(3-cyclopropyl-4-fluorophenyl)pyridin-3-yl)-1,5-naphthyridine(Compound 216). LCMS: rt 5.81 min (A), MS (m/e) 342 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.03 (dd, J=4.5, 1.8 Hz, 1H), 8.85 (dd, J=5.4, 1.8 Hz, 1H),8.57-8.50 (m, 2H), 8.28 (dd, J=8.7, 0.9 Hz, 1H), 7.87 (m, 2H), 7.46 (d,J=8.7 Hz, 1H), 7.22 (m, 1H), 7.04 (dd, J=10.2, 8.7 Hz, 1H), 6.88 (dd,J=7.2, 2.4 Hz, 1H), 1.98 (m, 1H), 0.82 (m, 2H), 0.26 (m, 2H).

6-(2-(3-Cyclopropyl-4-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 217). LCMS: rt 5.35 min (A), MS (m/e) 331 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.81 (dd, J=1.8, 0.9 Hz, 1H), 8.45 (s, 1H), 8.18 (dd, J=7.8,1.8 Hz, 1H), 7.69-7.64 (m, 2H), 7.38 (dd, J=9.3, 1.8 Hz, 1H), 7.21 (m,1H), 7.01 (dd, J=9.9, 8.4 Hz, 1H), 6.92 (dd, J=7.2, 2.4 Hz, 1H), 2.03(m, 1H), 0.85 (m, 2H), 0.36 (m, 2H).

6-(2-(3-Cyclopropyl-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 218). LCMS: rt 4.23 min (A), MS (m/e) 330 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.85 (m, 1H), 8.85 (dd, J=4.8, 1.5 Hz, 1H), 8.22 (dd, J=2.1,0.9 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 8.04 (dd, J=7.8, 1.5 Hz, 1H), 7.80(m, 1H), 7.62-7.55 (m, 2H), 7.13 (m, 1H), 7.04 (dd, J=7.5, 2.4 Hz, 1H),6.95 (d, J=1.5 Hz, 1H), 2.03 (m, 1H), 0.92 (m, 2H), 0.48 (m, 2H).

N-(6-(4-Fluoro-3-methylphenyl)-5-(imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)morpholine-4-carboxamide(Compound 219). LCMS: rt 4.00 min (A), MS (m/e) 432 MH⁺.

1-Ethyl-3-(6-(4-fluoro-3-methylphenyl)-5-(imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)urea(Compound 220). LCMS: rt 4.01 min (A), MS (m/e) 390 MH⁺.

3-(6-(4-Fluoro-3-methylphenyl)-5-(imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)-1,1-dimethylurea(Compound 221). LCMS: rt 3.91 min (A), MS (m/e) 390 MH⁺.

(6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)methanol(Compound 222). LCMS: rt 5.16 min (b), MS (m/e) 346 MH⁺.

6-(2-(3-Cyclopropyl-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 223). LCMS: rt 5.90 min (A), MS (m/e) 355 MH⁺.

6-(2-(3-Cyclopropyl-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 224). LCMS: rt 4.28 min (A), MS (m/e) 373 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.69 (dd, J=1.8, 0.9 Hz, 1H), 8.79 (dd, J=5.1, 1.5 Hz, 1H),8.52 (s, 1H), 8.27 (dd, J=7.8, 1.8 Hz, 1H), 7.78 (m, 2H), 7.54 (dd,J=9.3, 1.5 Hz, 1H), 7.16 (m, 1H), 7.03 (dd, J=7.2, 2.1 Hz, 1H), 6.99(dd, J=10.2, 8.7 Hz, 1H), 2.03 (m, 1H), 0.92 (m, 2H), 0.51 (m, 2H).

4-(6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)methyl)morpholine(Compound 225). LCMS: rt 5.06 min (A), MS (m/e) 415 MH⁺.

1-(6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)-N,N-dimethylmethanamine(Compound 226). LCMS: rt 4.98 min (A), MS (m/e) 373 MH⁺.

6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)nicotinic acid (Compound227). LCMS: rt 6.33 min (A), MS (m/e) 360 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)-5-(methoxymethyl)pyridin-3-yl)quinoxaline(Compound 228). LCMS: rt 5.81 min (A), MS (m/e) 360 MH⁺.

6-(5-(Ethoxymethyl)-2-(4-fluoro-3-methylphenyl)pyridin-3-yl)quinoxaline(Compound 229). LCMS: rt 6.18 min (A), MS (m/e) 374 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)-5-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)quinoxaline(Compound 230). LCMS: rt 4.60 min (A), MS (m/e) 428 MH⁺.

2-(6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)methoxy)-N,N-dimethylacetamide(Compound 231). LCMS: rt 5.41 min (A), MS (m/e) 431 MH⁺.

2-(6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)methoxy)-N-methylacetamide(Compound 232). LCMS: rt 5.36 min (A), MS (m/e) 417 MH⁺.

2-(6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)methoxy)acetamide(Compound 233). LCMS: rt 5.11 min (A), MS (m/e) 403 MH⁺.

6-(4-Fluoro-3-methylphenyl)-N,N-dimethyl-5-(quinoxalin-6-yl)nicotinamide(Compound 234). LCMS: rt 6.38 min (A), MS (m/e) 387 MH⁺.

6-(4-Fluoro-3-methylphenyl)-N-methyl-5-(quinoxalin-6-yl)nicotinamide(Compound 235). LCMS: rt 6.28 min (A), MS (m/e) 373 MH⁺.

6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)(morpholino)methanone(Compound 236). LCMS: rt 6.41 min (A), MS (m/e) 429 MH⁺.

(6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone(Compound 237). LCMS: rt 4.98 min (A), MS (m/e) 442 MH⁺.

6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)nicotinamide (Compound238). LCMS: rt 5.98 min (A), MS (m/e) 359 MH⁺.

6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-amine (Compound239). LCMS: rt 4.81 min (A), MS (m/e) 331 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.93 (m, 2H), 8.09 (d, J=2.7 Hz, 1H), 8.05 (d, J=1.8 Hz, 1H), 8.04 (d,J=9.0 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.62 (dd, J=8.7, 1.8 Hz, 1H),7.32 (dd, J=7.2, 2.1 Hz, 1H), 7.07 (m, 1H), 6.96 (m, 1H), 2.18 (s, 3H).

6-(4-Fluoro-3-methylphenyl)-N-(1-methylpiperidin-4-yl)-5-(quinoxalin-6-yl)pyridin-3-amine(Compound 240). LCMS: rt 4.26 min (A), MS (m/e) 428 MH⁺.

6-(4-Fluoro-3-methylphenyl)-N-isopropyl-5-(quinoxalin-6-yl)pyridin-3-amine(Compound 241). LCMS: rt 5.56 min (A), MS (m/e) 373 MH⁺.

N,N-Diethyl-6-(4-fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-amine(Compound 242). LCMS: rt 5.75 min (A), MS (m/e) 387 MH⁺.

2-(6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)amino)cyclohexan-1-ol(Compound 243). LCMS: rt 5.41 min (A), MS (m/e) 429 MH⁺.

6-(4-Fluoro-3-methylphenyl)-N-(pyridin-3-ylmethyl)-5-(quinoxalin-6-yl)pyridin-3-amine(Compound 244). LCMS: rt 4.28 min (A), MS (m/e) 422 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.91 (m, 3H), 8.75 (d, J=4.5 Hz, 1H), 8.53 (dd, J=8.4, 1.5 Hz,1H), 8.17 (d, J=2.7 Hz, 1H), 8.01 (m, 2H), 7.95 (dd, J=7.8, 5.7 Hz, 1H),7.84 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.4, 1.8 Hz, 1H), 7.31 (dd, J=7.8,1.8 Hz, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 4.81 (s, 2H), 2.17 (s, 3H).

6-(4-Fluoro-3-methylphenyl)-N-(pyridin-4-ylmethyl)-5-(quinoxalin-6-yl)pyridin-3-amine(Compound 245). LCMS: rt 4.26 min (A), MS (m/e) 422 MH⁺.

6-(4-Fluoro-3-methylphenyl)-N-(pyridin-2-ylmethyl)-5-(quinoxalin-6-yl)pyridin-3-amine(Compound 246). LCMS: rt 4.43 min (A), MS (m/e) 422 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(1-methylpiperidin-4-yl)pyridin-3-amine(Compound 247). LCMS: rt 4.56 min (A), MS (m/e) 433 MH⁺.

6-(2-m-Tolylpyridin-3-yl)isoquinoline (Compound 248).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)isoquinoline (Compound 249)

4-(3-(6-(2-m-Tolylpyridin-3-yl)-1H-benzo[d]imidazol-1-yl)propyl)morpholine(Compound 250).

1-(3-(4-Methylpiperazin-1-yl)propyl)-6-(2-m-tolylpyridin-3-yl)-1H-benzo[d]imidazole(Compound 251).

4-(3-(6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)propyl)morpholine(Compound 252).

1-(3-(4-Methylpiperazin-1-yl)propyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-benzo[d]imidazole(Compound 253).

2-Fluoro-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 254). Anhydrous THF (25 mL) was introduced to a mixture of6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine (0.42g) and NaH (165 mg, 60% in mineral oil) under argon. The reactionmixture was stirred for 10 min and Selectofluor™ (750 mg) as solid wasadded in portions for 10 min. After complete addition of Selectofluor™,the reaction mixture was heated at 60° C. After 8h, the reaction mixturewas cooled to room temperature and additional amount of NaH (165 mg) andSelectofluor™ were added to the brown reaction mixture and continued toheat at 60° C. overnight. The reaction mixture was cooled with ice-bath,quenched with water slowly and concentrated. Usual work-up andpurification by reverse phase preparative HPLC provided2-fluoro-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridineas a pale yellow solid (23 mg). ¹H NMR (300 MHz, DMSO-d₆) δ 8.74-8.56(m, 1H), 8.31 (dd, J=1.9, 1.0 Hz, 1H), 7.92 (dt, J=7.7, 1.3 Hz, 1H),7.56-7.35 (m, 3H), 7.35-7.21 (m, 2H), 7.06 (ddd, J=8.1, 5.2, 2.3 Hz,1H), 6.94 (dd, J=9.8, 8.4 Hz, 1H), 6.68 (dt, J=9.5, 1.3 Hz, 1H), 2.12(s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −118.22, −157.61 (d, J=7.1 Hz).LCMS: purity 99%, MS (m/e) 322 MH⁺.

Ethyl7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(Compound 255). ¹H NMR (300 MHz, DMSO-d₆) δ 9.03 (d, J=7.4 Hz, 1H), 8.70(dd, J=4.7, 1.7 Hz, 1H), 7.95 (dd, J=7.8, 1.7 Hz, 1H), 7.86 (d, J=1.7Hz, 1H), 7.69 (s, 1H), 7.56-7.41 (m, 2H), 7.13-6.93 (m, 2H), 6.71 (dd,J=7.5, 1.8 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.17 (s, 3H), 1.33 (t, J=7.1Hz, 3H). LCMS: rt5.83 min (B), purity 96%, MS (m/e) 376 MH⁺.

Ethyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(Compound 256). LCMS: rt5.81 min (B), purity 98%, MS (m/e) 376 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylicacid (Compound 257). ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (q, J=1.2 Hz, 1H),8.71 (dd, J=4.8, 1.7 Hz, 1H), 7.97 (dd, J=7.8, 1.7 Hz, 1H), 7.77-7.57(m, 2H), 7.52 (dd, J=7.8, 4.8 Hz, 1H), 7.48-7.38 (m, 1H), 7.10 (ddd,J=8.0, 5.1, 2.3 Hz, 1H), 6.97 (dd, J=9.7, 8.5 Hz, 1H), 6.75 (dd, J=9.2,1.5 Hz, 1H), 2.16 (s, 3H). LCMS: rt4.11 min (A), purity 96%, MS (m/e)348 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylicacid (Compound 258). ¹H NMR (300 MHz, DMSO-d₆) δ 9.19-8.96 (m, 1H), 8.68(dd, J=4.8, 1.6 Hz, 1H), 7.94 (dd, J=7.8, 1.7 Hz, 1H), 7.80 (d, J=1.9Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.56-7.37 (m, 2H), 7.16-6.88 (m, 2H),6.63 (dt, J=7.5, 1.7 Hz, 1H), 2.17 (s, 3H). LCMS: rt3.93 min (A), purity95%, MS (m/e) 348 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 259). ¹H NMR (300 MHz, DMSO-d₆) δ 9.42 (t, J=1.3 Hz, 1H),8.88-8.54 (m, 2H), 8.24 (d, J=1.1 Hz, 0H), 7.93 (dt, J=7.8, 1.4 Hz, 1H),7.59 (dd, J=9.3, 1.2 Hz, 1H), 7.55-7.35 (m, 3H), 7.11 (td, J=6.3, 4.9,3.0 Hz, 1H), 6.97 (t, J=9.1 Hz, 1H), 6.60 (dt, J=9.4, 1.3 Hz, 1H), 3.31(q, J=6.5 Hz, 2H), 2.33 (t, J=6.7 Hz, 2H), 2.16 (s, 3H), 2.14 (s, 3H),1.67 (p, J=6.8 Hz, 2H). LCMS: rt3.35 min (B), purity 99%, MS (m/e) 487MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 260). LCMS: rt3.54 min (B), purity 99%, MS (m/e) 473 MH⁺.

(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)((3-morpholinopropyl)-12-azanyl)methanone(Compound 261). LCMS: rt3.72 min (B), purity 99%, MS (m/e) 474 MH⁺.

N-(3-(Dimethylamino)propyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 262). LCMS: rt3.64 min (B), purity 99%, MS (m/e) 432 MH⁺.

N-(2-(Dimethylamino)ethyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 263). LCMS: rt3.57 min (B), purity 99%, MS (m/e) 418 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 264). ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (dt, J=7.5, 1.0 Hz,1H), 8.74 (t, J=5.8 Hz, 1H), 8.68 (dd, J=4.7, 1.7 Hz, 1H), 7.93 (dd,J=7.8, 1.7 Hz, 1H), 7.74 (dd, J=1.8, 1.1 Hz, 1H), 7.56 (d, J=0.8 Hz,1H), 7.52-7.39 (m, 2H), 7.21-6.90 (m, 2H), 6.55 (dd, J=7.5, 1.9 Hz, 1H),3.30 (q, J=6.5 Hz, 2H), 2.43-2.22 (m, 2H), 2.18 (s, 3H), 2.14 (s, 3H),1.66 (p, J=6.8 Hz, 2H). LCMS: rt3.25 min (B), purity 99%, MS (m/e) 487MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 265). LCMS: rt3.43 min (B), purity 99%, MS (m/e) 473 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-morpholinopropyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 266). LCMS: rt 3.62 min (B), purity 99%, MS (m/e) 474 MH⁺.

N-(3-(Dimethylamino)propyl)-7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 267). LCMS: rt3.53 min (B), purity 99%, MS (m/e) 432 MH⁺.

N-(2-(Dimethylamino)ethyl)-7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 268). LCMS: rt3.47 min (B), purity 99%, MS (m/e) 418 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine(Compound 269). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (dd, J=4.8, 1.5 Hz,1H), 8.38 (d, J=14.4 Hz, 2H), 7.91 (dd, J=7.8, 1.6 Hz, 1H), 7.55-7.42(m, 2H), 7.38 (d, J=9.5 Hz, 1H), 7.31 (s, 1H), 7.14 (ddd, J=7.8, 5.0,2.2 Hz, 1H), 7.00 (t, J=9.1 Hz, 1H), 6.31 (dd, J=9.4, 1.4 Hz, 1H), 2.17(s, 3H). LCMS: rt2.70 min (B), purity 99%, MS (m/e) 304 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 270). LCMS: rt5.94 min (B), purity 99%, MS (m/e) 472 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)imidazo[1,5-a]pyridine-3-carboxamide (Compound 271). LCMS: rt3.66min (B), purity 99%, MS (m/e) 460 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(pyrrolidin-1-yl)ethyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 272). LCMS: rt3.74 min (B), purity 99%, MS (m/e) 445 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 273). LCMS: rt3.81 min (B), purity 99%, MS (m/e) 458 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 274). LCMS: rt5.88 min (B), purity 99%, MS (m/e) 472 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)imidazo[1,5-a]pyridine-3-carboxamide (Compound 275). LCMS: rt3.58min (B), purity 99%, MS (m/e) 460 MH⁺.

N-(2-Acetamidoethyl)-7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 276). LCMS: rt5.21 min (B), purity 99%, MS (m/e) 432 MH⁺.

N-(3-(1H-Imidazol-1-yl)propyl)-7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 277). LCMS: rt3.70 min (B), purity 99%, MS (m/e) 455 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 278). LCMS: rt3.71 min (B), purity 99%, MS (m/e) 457 MH⁺.

N-((1R,2R,3S,4S)-3-Carbamoylbicyclo[2.2.1]hept-5-en-2-yl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 279). LCMS: rt6.67 min (B), purity 99%, MS (m/e) 482 MH⁺.

N-((1R,2R,3S,4S)-3-Carbamoylbicyclo[2.2.1]hept-5-en-2-yl)-7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxamide(Compound 280). LCMS: rt6.65 min (B), purity 99%, MS (m/e) 482 MH⁺.

4-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)benzenesulfonamide(Compound 281). ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (d, J=4.7 Hz, 1H), 8.46(s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.7 Hz, 3H), 7.69 (d, J=7.0Hz, 2H), 7.58 (d, J=9.3 Hz, 1H), 7.54-7.39 (m, 4H), 7.03 (dt, J=9.2, 4.6Hz, 2H), 2.21 (s, 3H). LCMS: rt3.16 min (B), purity 99%, MS (m/e) 459MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-(pyridin-4-yl)imidazo[1,5-a]pyridine(Compound 282). LCMS: rt3.73 min (B), purity 99%, MS (m/e) 381 MH⁺.

3-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)aniline(Compound 283). LCMS: rt3.95 min (B), purity 99%, MS (m/e) 395 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-(3-methoxyphenyl)imidazo[1,5-a]pyridine(Compound 284). LCMS: rt5.35 min (B), purity 99%, MS (m/e) 410 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridin-3-amine(Compound 285). ¹H NMR (300 MHz, DMSO-d₆) δ 8.74-8.57 (m, 1H), 8.22 (d,J=2.1 Hz, 1H), 7.93-7.78 (m, 2H), 7.47 (qd, J=5.3, 4.7, 2.9 Hz, 2H),7.19 (dd, J=5.5, 2.8 Hz, 1H), 7.03 (ddd, J=10.3, 8.5, 1.7 Hz, 2H), 6.82(s, 1H), 5.98-5.79 (m, 2H), 2.20 (s, 3H). LCMS: rt2.78 min (B), purity99%, MS (m/e) 319 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-(3-methoxyphenyl)imidazo[1,5-a]pyridine(Compound 286). LCMS: rt5.36 min (B), purity 99%, MS (m/e) 410 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-(pyridin-4-yl)imidazo[1,5-a]pyridine(Compound 287). ¹H NMR (300 MHz, DMSO-d₆) δ 8.66 (dt, J=4.4, 2.1 Hz,1H), 8.33 (dd, J=4.4, 2.0 Hz, 1H), 8.22 (s, 1H), 8.07-7.85 (m, 1H),7.59-7.38 (m, 5H), 7.19 (ddt, J=7.6, 5.0, 2.4 Hz, 1H), 7.13-6.94 (m,3H), 6.62 (td, J=5.0, 2.4 Hz, 1H), 6.55-6.35 (m, 1H), 2.21 (s, 3H).LCMS: rt3.36 min (B), purity 99%, MS (m/e) 381 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-(4-methoxyphenyl)imidazo[1,5-a]pyridine(Compound 288). LCMS: rt4.73 min (B), purity 99%, MS (m/e) 410 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-phenylimidazo[1,5-a]pyridine(Compound 289). LCMS: rt5.09 min (B), purity 95%, MS (m/e) 380 MH⁺.

3-(7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)aniline(Compound 290). LCMS: rt4.38 min (A), purity 97%, MS (m/e) 395 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine(Compound 291). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (dd, J=4.7, 1.6 Hz,1H), 8.56 (dt, J=1.8, 0.7 Hz, 1H), 8.00-7.90 (m, 1H), 7.63 (dd, J=7.3,2.0 Hz, 1H), 7.52 (dd, J=7.8, 4.7 Hz, 1H), 7.33-7.18 (m, 3H), 7.05 (dd,J=9.1, 1.8 Hz, 1H), 6.04 (s, 2H). LCMS: rt5.35 min (B), purity 99%, MS(m/e) 340 MH⁺.

7-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one(Compound 292). ¹H NMR (300 MHz, DMSO-d₆) δ 9.37 (s, 1H), 8.05-7.90 (m,2H), 7.31-7.15 (m, 5H), 4.86 (s, 2H), 2.10 (s, 3H). LCMS: rt7.13 min(A), purity 99%, MS (m/e) 392 MH⁺.

6-(4-Fluoro-3-methylphenyl)-7-(quinolin-6-yl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one(Compound 293). LCMS: rt5.10 min (A), purity 99%, MS (m/e) 386 MH⁺.

7-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one(Compound 294). LCMS: rt 7.83 min (A), purity 99%, MS (m/e) 406 MH⁺.

7-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine(Compound 295). ¹H NMR (300 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.05 (d, J=1.7Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.26-7.12 (m, 2H), 7.02 (s, 1H),6.90-6.68 (m, 2H), 4.41 (t, J=8.9 Hz, 2H), 3.37-3.24 (m, 2H), 2.90 (s,3H), 2.09 (s, 3H). LCMS: rt7.35 min (A), purity 99%, MS (m/e) 392 MH⁺.

6-(4-Fluoro-3-methylphenyl)-1-methyl-7-(quinolin-6-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine(Compound 296). LCMS: rt5.41 min (A), purity 99%, MS (m/e) 386 MH⁺.

7-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)isoquinolin-1-amine (Compound297). LCMS: rt5.11 min (A), purity 99%, MS (m/e) 350 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)isoquinolin-1-amine (Compound298). ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (dd, J=4.7, 1.7 Hz, 1H), 8.21 (s,1H), 7.87 (dd, J=7.8, 1.7 Hz, 1H), 7.73 (d, J=5.8 Hz, 1H), 7.54-7.38 (m,2H), 7.34 (dd, J=7.5, 2.0 Hz, 1H), 7.10 (dd, J=8.4, 1.7 Hz, 1H),6.96-6.82 (m, 2H), 6.79 (d, J=5.9 Hz, 1H), 6.71 (s, 2H), 2.08 (s, 3H).LCMS: rt4.38 min (A), purity 97%, MS (m/e) 330 MH⁺.

7-(2-(3-Fluorophenyl)pyridin-3-yl)isoquinolin-1-amine (Compound 299).LCMS: rt4.78 min (A), purity 98%, MS (m/e) 332 MH⁺.

6-(4-Fluoro-3-methylphenyl)-7-(1H-indazol-5-yl)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine(Compound 300). LCMS: rt6.80 min (B), purity 96%, MS (m/e) 375 MH⁺.

5-(2-(3-Chlorophenyl)pyridin-3-yl)thiazolo[5,4-b]pyridin-2-amine(Compound 301). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (dd, J=4.7, 1.6 Hz,1H), 8.02 (dd, J=7.8, 1.6 Hz, 1H), 7.86 (s, 2H), 7.55-7.45 (m, 2H),7.41-7.37 (m, 1H), 7.34 (ddd, J=7.8, 2.1, 1.1 Hz, 1H), 7.25 (t, J=7.8Hz, 1H), 7.09 (dt, J=7.7, 1.3 Hz, 1H), 7.00 (dd, J=8.2, 0.8 Hz, 1H).LCMS: rt4.85 min (A), purity 99%, MS (m/e) 339 MH⁺.

5-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)thiazolo[5,4-b]pyridin-2-amine(Compound 302). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (dd, J=4.7, 1.6 Hz,1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H), 7.87 (s, 2H), 7.55-7.45 (m, 3H), 7.28(t, J=7.8 Hz, 1H), 7.12 (ddd, J=8.6, 4.8, 2.2 Hz, 1H), 7.04 (dd, J=8.3,0.5 Hz, 1H). LCMS: rt5.26 min (A), purity 95%, MS (m/e) 357 MH⁺.

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)thiazolo[5,4-b]pyridine(Compound 303). ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (d, J=0.9 Hz, 1H), 8.73(ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.33 (dd, J=8.5, 0.8 Hz, 1H), 8.08 (ddd,J=7.9, 1.8, 0.9 Hz, 1H), 7.52 (ddd, J=7.8, 4.7, 0.9 Hz, 2H), 7.35 (ddd,J=7.9, 1.8, 0.8 Hz, 1H), 7.28 (dd, J=8.5, 0.9 Hz, 1H), 7.01-6.85 (m,3H), 2.13 (s, 3H). LCMS: rt5.53 min (A), purity 99%, MS (m/e) 322 MH⁺.

5-(2-(m-Tolyl)pyridin-3-yl)thiazolo[5,4-b]pyridine (Compound 304). LCMS:rt3.37 min (A), purity 96%, MS (m/e) 304 MH⁺.

5-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)thiazolo[5,4-b]pyridine(Compound 305). ¹H NMR (300 MHz, DMSO-d₆) δ 9.56 (s, 1H), 8.76 (dd,J=4.7, 1.7 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.12 (dd, J=7.8, 1.7 Hz,1H), 7.68-7.50 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.25 (t, J=9.0 Hz, 1H),7.09 (ddd, J=8.7, 4.8, 2.2 Hz, 1H). LCMS: rt6.76 min (A), purity 96%, MS(m/e) 342 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(pyridin-3-ylmethyl)pyridin-3-amine(Compound 306). LCMS: rt 4.48 min (A), MS (m/e) 427 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.29 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.79 (d, J=5.7 Hz, 1H),8.60 (dd, J=7.8, 1.5 Hz, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.03-7.91 (m, 3H),7.85 (d, J=3.0 Hz, 1H), 7.33 (dd, J=8.4, 1.8 Hz, 1H), 7.21 (dd, J=7.5,1.8 Hz, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 4.83 (s, 2H), 2.18 (s, 3H).

4-(((6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)amino)methyl)benzamide(Compound 307). LCMS: rt 4.41 min (A), MS (m/e) 464 MH⁺.

4-(((6-(4-Fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)pyridin-3-yl)amino)methyl)benzonitrile(Compound 308). LCMS: rt 5.81 min (A), MS (m/e) 446 MH⁺.

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)benzonitrile(Compound 309). LCMS: rt 5.85 min (A), MS (m/e) 451 MH⁺.

4-((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)benzamide(Compound 310). LCMS: rt 5.53 min (A), MS (m/e) 455 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(pyridin-4-yl)pyridin-3-amine(Compound 311). LCMS: rt 4.53 min (A), MS (m/e) 413 MH⁺.

N-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)-3-morpholinopropanamide(Compound 312). LCMS: rt 3.76 min (A), MS (m/e) 477 MH⁺.

N-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)-4-cyanobenzamide(Compound 313). LCMS: rt 7.59 min (A), MS (m/e) 465 MH⁺.

N-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)isonicotinamide(Compound 314). LCMS: rt 6.26 min (A), MS (m/e) 441 MH⁺.

N-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)nicotinamide(Compound 315). LCMS: rt 6.28 min (A), MS (m/e) 441 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.24 (s, 1H), 9.15 (dd, J=2.1, 0.9 Hz, 1H), 8.99 (d, J=2.4 Hz,1H), 8.75 (dd, J=8.4, 1.8 Hz, 1H), 8.39 (m, 2H), 7.98 (m, 2H), 7.67-7.53(m, 2H), 7.35 (dd, J=8.7, 1.8 Hz, 1H), 7.26 (dd, J=4.5, 1.8 Hz, 1H),7.02 (m, 1H), 6.84 (m, 1H), 2.13 (s, 3H);

N-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)butyramide(Compound 316). LCMS: rt 6.72 min (A), MS (m/e) 406 MH⁺.

N-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)-4-(pyridin-4-yl)butanamide(Compound 317). LCMS: rt 4.03 min (A), MS (m/e) 483 MH⁺.

4-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)benzamide(Compound 318). LCMS: rt 7.15 min (B), MS (m/e) 440 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)benzo[d]thiazole(Compound 319). LCMS: rt 3.86 min (B), MS (m/e) 419 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(3-(4-methylpiperazin-1-yl)propyl)pyridin-3-amine(Compound 320). LCMS: rt 2.72 min (A), MS (m/e) 476 MH⁺.

5-(Benzo[d]thiazol-6-yl)-N-((6-chloropyridin-3-yl)methyl)-6-(4-fluoro-3-methylphenyl)pyridin-3-amine(Compound 321). LCMS: rt 6.08 min (A), MS (m/e) 461 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.30 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.04-7.98 (m, 3H), 7.92(dd, J=8.1, 2.7 Hz, 1H), 7.80 (d, J=3.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H),7.32 (dd, J=8.4, 2.1 Hz, 1H), 7.25 (dd, J=7.2, 1.8 Hz, 1H), 7.04 (m,1H), 6.95 (m, 1H), 4.60 (s, 2H), 2.18 (s, 3H);

N-((1H-Imidazol-5-yl)methyl)-5-(benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-amine(Compound 322). LCMS: rt 3.47 min (B), MS (m/e) 416 MH⁺.

5-(Benzo[d]thiazol-6-yl)-N-((2-ethyl-1H-imidazol-5-yl)methyl)-6-(4-fluoro-3-methylphenyl)pyridin-3-amine(Compound 323). LCMS: rt 3.63 min (B), MS (m/e) 444 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-((6-methoxypyridin-3-yl)methyl)pyridin-3-amine(Compound 324). LCMS: rt 5.46 min (A), MS (m/e) 457 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.24 (s, 1H), 8.16 (d, J=1.8 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H),7.92 (d, J=8.7 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.4, 2.4 Hz,1H), 7.27 (dd, J=8.4, 1.8 Hz, 1H), 7.12 (m, 2H), 6.92-6.74 (m, 3H), 4.38(s, 2H), 3.88 (s, 3H), 2.10 (s, 3H);

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-((5-methoxypyridin-3-yl)methyl)pyridin-3-amine(Compound 325). LCMS: rt 4.43 min (A), MS (m/e) 457 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(thiazol-2-ylmethyl)pyridin-3-amine(Compound 326). LCMS: rt 5.64 min (B), MS (m/e) 433 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.16 (s, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H),7.81 (m, 1H), 7.74 (d, J=3.0 Hz, 1H), 7.46 (d, J=3.3 Hz, 1H), 7.26 (dd,J=8.4, 1.8 Hz, 1H), 7.15 (dd, J=7.5, 1.8 Hz, 1H), 7.12 (d, J=2.7 Hz,1H), 6.87 (m, 1H), 6.79 (m, 1H), 4.76 (s, 2H), 2.12 (s, 3H);

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(thiazol-5-ylmethyl)pyridin-3-amine(Compound 327). LCMS: rt 5.34 min (B), MS (m/e) 433 MH⁺.

N-([2,3′-Bipyridin]-5-ylmethyl)-5-(benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-amine(Compound 328). LCMS: rt 4.78 min (A), MS (m/e) 504 MH⁺.

N-((1H-Pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-(benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-amine(Compound 329). LCMS: rt 4.97 min (B), MS (m/e) 466 MH⁺.

N-((1H-Pyrrolo[2,3-b]pyridin-3-yl)methyl)-5-(benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-amine(Compound 330). LCMS: rt 4.74 min (B), MS (m/e) 466 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-((2-methylpyridin-3-yl)methyl)pyridin-3-amine(Compound 331). LCMS: rt 3.62 min (B), MS (m/e) 441 MH⁺.

3-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)phenol(Compound 332). LCMS: rt 5.29 min (B), MS (m/e) 442 MH⁺.

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)phenol(Compound 333). LCMS: rt 4.76 min (A), MS (m/e) 442 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-((6-methylpyridin-3-yl)methyl)pyridin-3-amine(Compound 334). LCMS: rt 3.68 min (B), MS (m/e) 441 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methyl)pyridin-3-amine(Compound 335). LCMS: rt 4.50 min (B), MS (m/e) 481 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.19 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.32 (s, 1H), 8.12 (d,J=1.5 Hz, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.83 (d,J=1.5 Hz, 1H), 7.23 (dd, J=8.7, 1.8 Hz, 1H), 7.14 (d, J=2.7 Hz, 1H),7.10 (dd, J=8.7, 1.8 Hz, 1H), 6.87 (m, 1H), 6.78 (m, 1H), 4.61 (s, 2H),3.90 (s, 3H), 2.08 (s, 3H).

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(quinolin-8-ylmethyl)pyridin-3-amine(Compound 336). LCMS: rt 6.02 min (B), MS (m/e) 477 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.19 (s, 1H), 8.34 (dd, J=8.1, 1.8 Hz, 1H), 8.04 (d, J=2.4 Hz,1H), 7.85 (m, 3H), 7.14 (d, J=1.2 Hz, 1H), 7.55 (m, 2H), 7.19 (dd,J=8.7, 1.8 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 7.10 (dd, J=7.8, 2.1 Hz,1H), 6.86 (m, 1H), 6.78 (m, 1H), 5.09 (s, 2H), 2.09 (s, 3H);

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(isoquinolin-5-ylmethyl)pyridin-3-amine (Compound 337). LCMS: rt 4.47 min(B), MS (m/e) 477 MH⁺.

N-(4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)phenyl)acetamide(Compound 338). LCMS: rt 5.14 min (B), MS (m/e) 483 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(quinolin-3-ylmethyl)pyridin-3-amine(Compound 339). LCMS: rt 5.41 min (B), MS (m/e) 477 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-methylquinazolin-4(3H)-one(Compound 340). LCMS: rt 4.70 min (A), MS (m/e) 346 MH⁺.

3-Methyl-6-(2-(m-tolyl)pyridin-3-yl)quinazolin-4(3H)-one (Compound 341).LCMS: rt 4.08 min (A), MS (m/e) 328 MH⁺.

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-3-methylquinazolin-4 (3H)-one(Compound 342). LCMS: rt 4.69 min (A), MS (m/e) 354 MH⁺.

3-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)phenol(Compound 343). LCMS: rt 6.83 min (A), MS (m/e) 413 MH⁺.

N-(3-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)phenyl)acetamide(Compound 344). LCMS: rt 6.65 min (A), MS (m/e) 454 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)-5-(1H-pyrazol-4-yl)pyridin-3-yl)benzo[d]thiazole(Compound 345). LCMS: rt 5.70 min (A), MS (m/e) 387 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4(1H)-one(Compound 346). LCMS: rt 3.79 min (A), MS (m/e) 332 MH⁺.

3-(5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)benzenesulfonamide(Compound 347). LCMS: rt 6.93 min (A), MS (m/e) 476 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4(1H)-one(Compound 348). LCMS: rt 4.45 min (A), MS (m/e) 332 MH⁺.

7-(2-(m-Tolyl)pyridin-3-yl)quinazolin-4(1H)-one (Compound 349). LCMS: rt4.08 min (A), MS (m/e) 314 MH⁺.

7-(2-(3-cyclopropylphenyl)pyridin-3-yl)quinazolin-4(1H)-one (Compound350). LCMS: rt 4.56 min (A), MS (m/e) 340 MH⁺.

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)-2-methoxyphenol(Compound 351). LCMS: rt 4.52 min (A), MS (m/e) 472 MH⁺.

2-(5-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)-2-methoxyphenoxy)acetamide(Compound 352). LCMS: rt 4.26 min (A), MS (m/e) 529 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.21 (s, 1H), 8.00 (d, J=2.7 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H),7.82 (m, 1H), 7.23 (dd, J=8.4, 1.8 Hz, 1H), 7.11-7.04 (m, 4H), 7.05 (d,J=2.7 Hz, 1H), 6.86 (m, 1H), 6.78 (m, 1H), 4.47 (s, 2H), 4.35 (s, 2H),3.84 (s, 3H), 2.09 (s, 3H).

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(4-morpholinobenzyl)pyridin-3-amine(Compound 353). LCMS: rt 5.03 min (A), MS (m/e) 511 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(3-morpholinobenzyl)pyridin-3-amine(Compound 354). LCMS: rt 5.13 min (A), MS (m/e) 511 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)-5-(1H-pyrazol-1-yl)pyridin-3-yl)benzo[d]thiazole(Compound 355). LCMS: rt 6.85 min (A), MS (m/e) 387 MH⁺.

2-(4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)-2-methoxyphenoxy)ethan-1-ol(Compound 356). LCMS: rt 4.41 min (A), MS (m/e) 516 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyridin-3-amine(Compound 357). LCMS: rt 5.51 min (A), MS (m/e) 526 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(4-(morpholinomethyl)benzyl)pyridin-3-amine(Compound 358). LCMS: rt 3.05 min (A), MS (m/e) 525 MH⁺.

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)benzenesulfonamide(Compound 359). LCMS: rt 4.34 min (A), MS (m/e) 505 MH⁺.

N-((2-Ethyl-1H-imidazol-5-yl)methyl)-6-(4-fluoro-3-methylphenyl)-5-(imidazo[1,2-a]pyridin-6-yl)pyridin-3-amine(Compound 360). LCMS: rt 3.56 min (A), MS (m/e) 427 MH⁺.

6-(2-(m-tolyl)pyridin-3-yl)quinazolin-4(1H)-one (Compound 361). LCMS: rt4.21 min (B), MS (m/e) 314 MH⁺.

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)quinazolin-4(1H)-one (Compound362). LCMS: rt 4.84 min (B), MS (m/e) 340 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazoline (Compound 363).LCMS: rt 3.81 min (A), MS (m/e) 316 MH⁺. ¹H NMR (CD₃OD, 300 MHz): 8.82(dd, J=5.4, 1.2 Hz, 1H), 8.54 (m, 1H), 8.38 (d, J=2.1 Hz, 1H), 7.98 (dd,J=8.1, 5.7 Hz, 1H), 7.64 (s, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 7.06 (m,2H), 2.22 (s, 3H).

6-(2-(m-Tolyl)pyridin-3-yl)quinazoline (Compound 364). LCMS: rt 3.46 min(A), MS (m/e) 298 MH⁺.

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)quinazoline (Compound 365). LCMS:rt 3.98 min (A), MS (m/e) 324 MH⁺. ¹H NMR (CD₃OD, 300 MHz): 8.78 (dd,J=5.4, 1.5 Hz, 1H), 8.45 (dd, J=7.8, 1.5 Hz, 1H), 8.25 (d, J=2.1 Hz,1H), 7.93 (dd, J=8.1, 5.7 Hz, 1H), 7.59 (m, 1H), 7.32-7.12 (m, 4H), 7.01(m, 2H), 1.84 (m, 1H), 0.85 (m, 2H), 0.45 (m, 2H).

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)-2,6-dimethoxyphenol(Compound 366). LCMS: rt 5.18 min (B), MS (m/e) 502 MH⁺.

5-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)-2,3-dimethoxyphenol(Compound 367). LCMS: rt 5.34 min (B), MS (m/e) 502 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.16 (s, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H),7.80 (bs, 1H), 7.25 (dd, J=8.4, 1.5 Hz, 1H), 7.13 (dd, J=7.5, 2.1 Hz,1H), 7.05 (d, J=2.7 Hz, 1H), 7.90 (m, 1H), 6.78 (m, 1H), 6.58 (m, 2H),4.32 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 2.11 (s, 3H);

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)benzene-1,2-diol(Compound 368). LCMS: rt 4.82 min (A), MS (m/e) 458 MH⁺.

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)-2-fluorophenol(Compound 369). LCMS: rt 5.48 min (B), MS (m/e) 460 MH⁺.

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)-2-(trifluoromethyl)phenol(Compound 370). LCMS: rt 6.32 min (B), MS (m/e) 510 MH⁺.

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)-2-(trifluoromethoxy)phenol(Compound 371). LCMS: rt 6.38 min (B), MS (m/e) 526 MH⁺. ¹H NMR (CD₃OD,300 MHz): 9.19 (s, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H),7.80 (bs, 1H), 7.61-7.50 (m, 3H), 7.22 (m, 1H), 7.08 (d, J=2.7 Hz, 1H),7.05-6.95 (m, 2H), 6.75 (m, 1H), 4.33 (s, 3H), 2.08 (s, 3H);

4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)-2-methylphenol(Compound 372). LCMS: rt 5.70 min (B), MS (m/e) 456 MH⁺.

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(4-(4-methylpiperazin-1-yl)benzyl)pyridin-3-amine(Compound 373). LCMS: rt 3.71 min (B), MS (m/e) 524 MH⁺.

1-(4-(((5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)pyridin-3-yl)amino)methyl)phenyl)piperidin-4-ol(Compound 374). LCMS: rt 4.19 min (B), MS (m/e) 525 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-4-methoxyquinazoline(Compound 375). LCMS: rt 6.91 min (B), MS (m/e) 346 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.66 (dd, J=5.1, 1.5 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 8.07 (s,1H), 7.95 (m, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.59-7.49 (m, 2H), 7.26 (d,J=7.5 Hz, 1H), 7.04 (m, 1H), 6.86 (m, 1H), 4.20 (s, 3H), 2.18 (s, 3H).

4-Methoxy-6-(2-(m-tolyl)pyridin-3-yl)quinazoline (Compound 376). LCMS:rt 6.29 min (B), MS (m/e) 328 MH⁺.

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-4-methoxyquinazoline (Compound377). LCMS: rt 6.94 min (B), MS (m/e) 354 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.64 (m, 1H), 8.08 (m, 2H), 7.97 (m, 1H), 7.60-7.48 (m, 3H), 7.16-7.02(m, 3H), 6.91 (m, 1H), 4.17 (s, 3H), 1.77 (m, 1H), 0.84 (m, 2H), 0.38(m, 2H).

3-(3-(4-Methoxyquinazolin-6-yl)pyridin-2-yl)phenol (Compound 378). LCMS:rt 3.78 min (A), MS (m/e) 330 MH⁺.

6-(2-(3-Hydroxyphenyl)pyridin-3-yl)-3-methylquinazolin-4(3H)-one(Compound 379). LCMS: rt 3.80 min (B), MS (m/e) 330 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.62 (dd, J=4.8, 1.5 Hz, 1H), 8.28 (s, 1H), 8.16 (m, 1H), 7.97(dd, J=7.5, 1.5 Hz, 1H), 7.54 (m, 3H), 7.05 (m, 1H), 6.72 (m, 3H), 3.57(s, 3H);

N-(3-(3-(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)phenyl)acetamide(Compound 380). LCMS: rt 3.84 min (B), MS (m/e) 371 MH⁺.

6-(2-(4-Fluorophenyl)pyridin-3-yl)-3-methylquinazolin-4(3H)-one(Compound 381). LCMS: rt 5.03 min (B), MS (m/e) 332 MH⁺.

3-Methyl-6-(2-(quinolin-8-yl)pyridin-3-yl)quinazolin-4(3H)-one (Compound382). LCMS: rt 3.50 min (B), MS (m/e) 365 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-2-amine (Compound383). LCMS: rt 4.06 min (B), MS (m/e) 331 MH⁺.

6-(2-(m-Tolyl)pyridin-3-yl)quinazolin-2-amine (Compound 384). LCMS: rt3.53 min (B), MS (m/e) 313 MH⁺.

4-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)morpholine(Compound 385). LCMS: rt 4.28 min (A), MS (m/e) 401 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.81 (dd, J=5.7, 1.5 Hz, 1H), 8.65 (s, 1H), 8.45 (dd, J=8.1,1.5 Hz, 1H), 8.24 (dd, J=7.8, 1.5 Hz, 1H), 8.17 (m, 2H), 7.90 (m, 1H),7.63 (m, 1H), 7.44-7.36 (m, 1H), 7.18 (m, 1H), 7.03 (m, 1H), 3.89 (m,4H), 3.22 (m, 4H), 2.21 (s, 3H).

4-(6-(2-(m-Tolyl)pyridin-3-yl)quinazolin-4-yl)morpholine (Compound 386).LCMS: rt 3.83 min (A), MS (m/e) 383 MH⁺.

4-(6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)quinazolin-4-yl)morpholine(Compound 387). LCMS: rt 4.26 min (A), MS (m/e) 409 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazolin-4(1H)-one(Compound 388). LCMS: rt 5.16 min (A), MS (m/e) 352 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)quinazolin-4(1H)-one (Compound 389).LCMS: rt 4.76 min (A), MS (m/e) 334 MH⁺. ¹H NMR (CD₃OD, 300 MHz): 8.75(dd, J=5.1, 1.5 Hz, 1H), 8.23 (dd, J=8.1, 1.5 Hz, 1H), 8.17 (s, 1H),8.15 (m, 2H), 7.76 (dd, J=8.1, 5.1 Hz, 1H), 7.62 (m, 1H), 7.45 (m, 1H),7.37 (m, 1H), 7.36-7.18 (m, 2H).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-methylquinazolin-4(3H)-one(Compound 390). LCMS: rt 5.70 min (A), MS (m/e) 366 MH⁺. 1H NMR (CD3OD,300 MHz): 8.75-8.73 (m, 1H), 8.36 (s, 1H), 8.20 (dd, 1H), 8.14 (m, 1H),7.77-7.72 (m, 1H), 7.63 (m, 2H), 7.55 (dd, 1H), 7.28-7.22 (m, 1H), 7.19(d, 1H), 3.59 (s, 3H).

6-(2-(3-Chlorophenyl)pyridin-3-yl)-3-methylquinazolin-4(3H)-one(Compound 391). LCMS: rt 5.28 min (A), MS (m/e) 348 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.67 (dd, 1H), 8.31 (s, 1H), 8.13 (m, 1H), 8.01 (dd, 1H), 7.58(m, 3H), 7.38 (m, 1H), 7.28 (m, 1H), 7.23-7.14 (m, 2H), 3.58 (s, 3H).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound392). LCMS: rt 2.43 min (A), MS (m/e) 331 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 393).LCMS: rt 3.26 min (B), MS (m/e) 333 MH⁺. ¹H NMR (CD₃OD, 300 MHz): 8.65(dd, J=5.1, 1.8 Hz, 1H), 8.37 (s, 1H), 8.16 (m, 1H), 8.03 (dd, J=7.8,1.8 Hz, 1H), 7.59 (dd, J=7.8, 1.8 Hz, 2H), 7.31 (m, 1H), 7.23-7.13 (m,2H).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound394). LCMS: rt 3.47 min (B), MS (m/e) 351 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.67 (dd, J=4.8, 1.5 Hz, 1H), 8.38 (s, 1H), 8.16 (d, J=1.5 Hz, 1H), 8.01(dd, J=7.8, 1.5 Hz, 1H), 7.61-7.48 (m, 4H), 7.318-7.06 (m, 2H).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-4-methoxyquinazoline(Compound 395). LCMS: rt 6.42 min (A), MS (m/e) 366 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-2-amine (Compound396). LCMS: rt 4.39 min (B), MS (m/e) 331 MH⁺. ¹H NMR (CD₃OD, 300 MHz):9.05 (br, 1H), 8.65 (dd, J=5.1, 1.8 Hz, 1H), 7.95 (dd, J=7.8, 1.8 Hz,1H), 7.70 (d, J=8.4 Hz, 1H), 7.53 (m, 1H), 7.36 (m, 1H), 7.29 (m, 1H),7.08-7.02 (m, 2H), 6.87 (m, 1H), 2.15 (s, 3H).

N,N-Diethyl-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-amine(Compound 397). LCMS: rt 3.89 min (B), MS (m/e) 387 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N,N-diethylquinazolin-4-amine(Compound 398). LCMS: rt 4.22 min (B), MS (m/e) 407 MH⁺.

3-(3-(4-(Diethylamino)quinazolin-6-yl)pyridin-2-yl)phenol (Compound399). LCMS: rt 3.05 min (B), MS (m/e) 371 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-isopropylquinazolin-4-amine(Compound 400). LCMS: rt 3.85 min (B), MS (m/e) 373 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N-isopropylquinazolin-4-amine(Compound 401). LCMS: rt 4.17 min (B), MS (m/e) 393 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-propylquinazolin-4-amine(Compound 402). LCMS: rt 3.25 min (A), MS (m/e) 373 MH⁺.

N-Butyl-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-amine(Compound 403). LCMS: rt 3.65 min (A), MS (m/e) 387 MH⁺.

N-Cyclopropyl-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-amine(Compound 404). LCMS: rt 3.68 min (B), MS (m/e) 371 MH⁺.

N-Cyclopentyl-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-amine(Compound 405). LCMS: rt 4.30 min (B), MS (m/e) 399 MH⁺.

4-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)amino)benzamide(Compound 406). LCMS: rt 3.63 min (A), MS (m/e) 450 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(4-methoxyphenyl)quinazolin-4-amine(Compound 407). LCMS: rt 4.73 min (B), MS (m/e) 437 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(4-morpholinophenyl)quinazolin-4-amine(Compound 408). LCMS: rt 4.46 min (B), MS (m/e) 492 MH⁺.

4-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)amino)benzonitrile(Compound 409). LCMS: rt 6.52 min (B), MS (m/e) 432 MH⁺.

3-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)amino)benzamide(Compound 410). LCMS: rt 4.05 min (B), MS (m/e) 450 MH⁺.

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound411). LCMS: rt 3.13 min (B), MS (m/e) 339 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.65 (dd, J=4.8, 1.5 Hz, 1H), 8.37 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.03(dd, J=7.8, 1.5 Hz, 1H), 7.56-7.51 (m, 2H), 7.41 (dd, J=9.0, 2.1 Hz,1H), 7.15-7.04 (m, 3H), 6.89 (m, 1H), 1.76 (m, 1H), 0.79 (m, 2H), 0.34(m, 2H).

3-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-1,8-naphthyridine (Compound412). LCMS: rt 5.84 min (B), MS (m/e) 114 MH⁺.

3-(2-(3-Chlorophenyl)pyridin-3-yl)-1,8-naphthyridine (Compound 413).LCMS: rt 5.58 min (B), MS (m/e) 318 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(pyridin-3-yl)ethyl)quinazolin-4-amine(Compound 414). LCMS: rt 2.82 min (B), MS (m/e) 436 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(pyridin-4-ylmethyl)quinazolin-4-amine(Compound 415). LCMS: rt 2.78 min (B), MS (m/e) 422 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(pyridin-3-ylmethyl)quinazolin-4-amine(Compound 416). LCMS: rt 3.03 min (B), MS (m/e) 422 MH⁺.

3-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1,8-naphthyridine (Compound417). LCMS: rt 5.23 min (B), MS (m/e) 316 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinoline-2-carbonitrile(Compound 418). LCMS: rt 7.75 min (B), MS (m/e) 340 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinoline-2-carbonitrile(Compound 419). LCMS: rt 8.26 min (B), MS (m/e) 360 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)quinoline-2-carbonitrile (Compound420). LCMS: rt 8.07 min (B), MS (m/e) 342 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-((1-methylpiperidin-4-yl)methyl)quinazolin-4-amine(Compound 421). LCMS: rt 2.32 min (B), MS (m/e) 442 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(1-methylpiperidin-4-yl)ethyl)quinazolin-4-amine(Compound 422). LCMS: rt 1.97 min (A), MS (m/e) 456 MH⁺.

N1-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine(Compound 423). LCMS: rt 3.55 min (A), MS (m/e) 416 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.79 (s, 1H), 8.67 (dd, J=5.4, 1.5 Hz, 1H), 8.49 (m, 1H), 8.21(dd, J=7.8, 1.8 Hz, 1H), 7.77 (dd, J=8.1, 5.4 Hz, 1H), 7.66 (m, 2H),7.37 (m, 1H), 7.09 (m, 1H), 6.94 (m, H), 3.94 (t, J=6.6 Hz, 2H), 3.29(m, 2H), 2.91 (s, 6H), 2.24 (m, 2H), 2.20 (s, 3H);

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-morpholinopropyl)quinazolin-4-amine(Compound 424). LCMS: rt 3.61 min (A), MS (m/e) 458 MH⁺.

4-(2-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)oxy)ethyl)morpholine(Compound 425). LCMS: rt 3.42 min (B), MS (m/e) 445 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinolin-2-amine (Compound426). LCMS: rt 3.19 min (B), MS (m/e) 330 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinolin-2-amine (Compound427). LCMS: rt 3.72 min (B), MS (m/e) 350 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)quinolin-2-amine (Compound 428). LCMS:rt 3.50 min (B), MS (m/e) 332 MH⁺.

3-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)oxy)-N,N-dimethylpropan-1-amine(Compound 429). LCMS: rt 3.47 min (B), MS (m/e) 417 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.74 (s, 1H), 8.66 (dd, J=5.1, 1.5 Hz, 1H), 8.10 (m, 1H), 8.03(dd, J=7.8, 1.5 Hz, 1H), 7.77 (m, 1H), 7.67 (dd, J=7.8, 5.1 Hz, 1H),7.56 (m, 2H), 7.27 (m, 1H), 7.06 (m, 1H), 6.88 (m, H), 4.67 (t, J=6.0Hz, 2H), 2.88 (m, 2H), 2.56 (s, 6H), 2.21 (m, 2H), 2.14 (s, 3H).

2-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)oxy)acetonitrile(Compound 430). LCMS: rt 6.76 min (B), MS (m/e) 371 MH⁺.

1-(3-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)oxy)propyl)pyrrolidin-2-one(Compound 431). LCMS: rt 4.92 min (A), MS (m/e) 457 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-4-((6-methylpyridin-3-yl)oxy)quinazoline(Compound 432). LCMS: rt 6.58 min (B), MS (m/e) 423 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.69 (s, 1H), 8.67 (dd, J=5.4, 1.8 Hz, 1H), 8.35 (dd, J=7.8,1.5 Hz, 1H), 8.16 (m, 1H), 8.07 (m, 1H), 7.70 (m, 2H), 7.57 (m, 2H),7.27-7.02 (m, 3H), 6.89 (m, 1H), 2.41 (s, 3H), 2.18 (s, 3H).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-4-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline(Compound 433). LCMS: rt 3.45 min (B), MS (m/e) 458 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-4-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline(Compound 434). LCMS: rt 3.42 min (B), MS (m/e) 472 MH⁺.

3-((6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazolin-4-yl)oxy)-N,N-dimethylpropan-1-amine(Compound 435). LCMS: rt 3.83 min (B), MS (m/e) 437 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.74 (s, 1H), 8.65 (dd, J=5.4, 1.5 Hz, 1H), 8.10 (m, 2H), 8.03(dd, J=7.8, 1.5 Hz, 1H), 7.84 (m, 1H), 7.67 (dd, J=7.8, 5.1 Hz, 1H),7.56 (m, 1H), 7.20 (m, 1H), 7.12 (m, 1H), 4.66 (t, J=6.6 Hz, 2H), 2.77(m, 2H), 2.46 (s, 6H), 2.14 (m, 2H);

1-(3-((6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazolin-4-yl)oxy)propyl)pyrrolidin-2-one(Compound 436). LCMS: rt 6.60 min (B), MS (m/e) 477 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-4-((6-methylpyridin-3-yl)oxy)quinazoline(Compound 437). LCMS: rt 7.36 min (B), MS (m/e) 443 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.70 (s, 1H), 8.67 (dd, J=5.4, 1.5 Hz, 1H), 8.37 (dd, J=7.8,1.5 Hz, 1H), 8.15 (m, 2H), 8.08 (m, 2H), 7.96 (m, 1H), 7.57 (m, 2H),7.23-7.06 (m, 3H), 2.41 (s, 3H).

2-((6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazolin-4-yl)oxy)-N,N-diethylethan-1-amine(Compound 438). LCMS: rt 3.89 min (B), MS (m/e) 451 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.76 (s, 1H), 8.67 (dd, J=5.1, 1.5 Hz, 1H), 8.11 (dd, J=7.8,1.8 Hz, 1H), 7.99 (m, 1H), 7.82 (m, 1H), 7.59-7.48 (m, 3H), 7.21-7.05(m, 2H), 4.76 (t, J=2.4 Hz, 2H), 3.83 (t, J=2.4 Hz, 2H), 2.84 (q, J=7.2Hz, 4H), 1.30 (t, J=7.2 Hz, 6H).

2-((6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazolin-4-yl)oxy)-N,N-dimethylethan-1-amine(Compound 439). LCMS: rt 3.69 min (B), MS (m/e) 423 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.76 (s, 1H), 8.61 (dd, J=5.4, 1.5 Hz, 1H), 8.23 (m, 1H), 8.10(m, 1H), 8.01 (dd, J=7.8, 1.5 Hz, 1H), 7.86 (m, 1H), 7.65 (dd, J=7.8,5.1 Hz, 1H), 7.61 (m, 1H), 7.16 (m, 1H), 7.09 (m, 1H), 4.75 (t, J=5.7Hz, 2H), 3.80 (t, J=5.7 Hz, 2H), 2.78 (s, 6H).

4-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)oxy)benzonitrile(Compound 440). LCMS: rt 8.03 min (B), MS (m/e) 433 MH⁺.

3-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)oxy)benzonitrile(Compound 441). LCMS: rt 8.06 min (B), MS (m/e) 433 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-4-(pyridin-3-yloxy)quinazoline(Compound 442). LCMS: rt 6.66 min (B), MS (m/e) 409 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.70 (s, 1H), 8.67 (dd, J=4.8, 1.5 Hz, 1H), 8.15 (s, 1H), 8.07(m, 1H), 7.95 (dd, J=7.5, 1.5 Hz, 1H), 7.86 (m, 1H), 7.62-7.50 (m, 3H),7.59 (m, 1H), 7.35-7.23 (m, 2H), 7.03 (m, 1H), 6.88 (m, 1H), 2.19 (s,3H).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)quinazoline(Compound 443). LCMS: rt 2.87 min (A), MS (m/e) 429 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.65 (m, 1H), 8.14 (s, 1H), 7.96 (m, 2H), 7.78 (m, 1H),7.64-7.50 (m, 2H), 7.27 (m, 1H), 7.04 (m, 1H), 6.87 (m, 1H), 4.78 (t,J=5.4 Hz, 2H), 3.06 (t, J=5.4 Hz, 2H), 3.71 (m, 3H), 2.17 (s, 3H), 2.16(m, 2H), 1.87 (m, 3H);

4-(3-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)oxy)phenyl)morpholine(Compound 444). LCMS: rt 8.06 min (B), MS (m/e) 493 MH⁺.

5-(2-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-yl)oxy)ethyl)-4-methylthiazole(Compound 445). LCMS: rt 7.23 min (B), MS (m/e) 457 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.75 (s, 1H), 8.66 (dd, J=5.1, 1.8 Hz, 1H), 8.11 (s, 1H), 8.11(m, 1H), 7.99 (dd, J=6.9, 1.8 Hz, 1H), 7.77 (s, 1H), 7.57 (m, 2H), 7.27(m, 1H), 7.04 (m, 1H), 6.88 (m, 1H), 4.78 (t, J=6.0 Hz, 2H), 3.38 (t,J=6.0 Hz, 2H), 2.24 (s, 3H), 2.14 (s, 3H).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-4-(quinolin-6-yloxy)quinazoline(Compound 446). LCMS: rt 5.71 min (A), MS (m/e) 459 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.75-8.59 (m, 2H), 8.42 (s, 1H), 8.12 (m, 2H), 7.99 (dd,J=8.1, 1.8 Hz, 1H), 7.88 (m, 1H), 7.76 (s, 1H), 7.59 (m, 2H), 7.43-7.27(m, 3H), 7.25 (m, 1H), 7.06 (m, 1H), 6.88 (m, 1H), 2.17 (s, 3H).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-4-((1-(pyridin-4-yl)piperidin-4-yl)oxy)quinazoline(Compound 447). LCMS: rt 3.31 min (A), MS (m/e) 492 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.74 (s, 1H), 8.67 (dd, J=5.4, 1.8 Hz, 1H), 8.52 (s, 1H), 8.09(m, 3H), 7.98 (m, 1H), 7.87 (m, 1H), 7.57 (m, 2H), 7.25 (m, 1H),7.14-7.01 (m, 2H), 6.87 (m, 1H), 3.77 (m, 4H), 3.47 (m, 1H), 2.21 (s,3H), 1.96 (m, 4H).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound448). LCMS: rt 4.46 min (A), MS (m/e) 351 MH⁺. ¹H NMR (DMSO-d₆, 300MHz): 8.67 (dd, J=4.8, 1.5 Hz, 1H), 8.32 (s, 1H), 8.20 (d, J=2.1 Hz,1H), 7.91 (dd, J=7.5, 1.8 Hz, 1H), 7.69 (bs, 2H), 7.55-7.46 (m, 3H),7.36 (dd, J=8.4, 1.8 Hz, 1H), 7.16 (m, 1H), 7.09-7.04 (m, 1H).

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound449). LCMS: rt 4.51 min (A), MS (m/e) 351 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.79 (dd, J=4.8, 1.5 Hz, 1H), 8.67 (s, 1H), 8.34 (d, J=1.5 Hz, 1H), 8.13(dd, J=7.8, 1.5 Hz, 1H), 7.80 (dd, J=8.7, 1.8 Hz, 1H), 7.71 (m, 2H),7.64 (dd, J=6.3, 3.0 Hz, 1H), 7.42 (m, 1H), 6.92 (m, 1H).

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)quinazolin-4-amine(Compound 450). LCMS: rt 4.80 min (A), MS (m/e) 369 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.79 (dd, J=4.8, 1.5 Hz, 1H), 8.68 (s, 1H), 8.34 (d, J=1.8 Hz,1H), 8.10 (dd, J=7.2, 1.5 Hz, 1H), 7.83 (dd, J=7.5, 2.1 Hz, 1H), 7.79(m, 1H), 7.71 (m, 2H), 6.99 (m, 1H).

6-(2-(3-Methoxyphenyl)pyridin-3-yl)quinazolin-4-amine (Compound 451).LCMS: rt 3.26 min (A), MS (m/e) 329 MH⁺. ¹H NMR (CD₃OD, 300 MHz): 8.50(dd, J=5.4, 1.8 Hz, 1H), 8.68 (s, 1H), 8.43 (m, 2H), 7.94 (dd, J=8.1,5.4 Hz, 1H), 7.76 (dd, J=8.4, 1.8 Hz, 1H), 7.65 (m, 1H), 7.26 (m, 1H),7.01 (m, 2H), 6.88 (m, 1H), 3.71 (s, 3H).

6-(2-(3-(Trifluoromethoxy)phenyl)pyridin-3-yl)quinazolin-4-amine(Compound 452). LCMS: rt 4.71 min (A), MS (m/e) 383 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.80 (dd, J=5.1, 1.5 Hz, 1H), 8.69 (s, 1H), 8.36 (m, 1H), 8.18(dd, J=7.8, 1.8 Hz, 1H), 7.77-7.65 (m, 3H), 7.43 (m, 2H), 7.28 (m, 1H),7.19 (m, 2H).

6-(2-(3,4-Difluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 453).LCMS: rt 4.01 min (A), MS (m/e) 335 MH⁺. ¹H NMR (CD₃OD, 300 MHz): 8.76(dd, J=5.4, 1.5 Hz, 1H), 8.69 (s, 1H), 8.38 (m, 1H), 8.14 (dd, J=7.8,1.5 Hz, 1H), 7.70-7.65 (m, 2H), 7.35 (m, 2H), 7.18 (m, 1H), 7.09 (m,1H).

6-(2-(2,5-Difluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 454).LCMS: rt 4.11 min (A), MS (m/e) 335 MH⁺. ¹H NMR (CD₃OD, 300 MHz): 8.79(dd, J=4.8, 1.5 Hz, 1H), 8.67 (s, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.11 (dd,J=7.8, 1.8 Hz, 1H), 7.82 (dd, J=8.4, 1.5 Hz, 1H), 7.79-7.65 (m, 2H),7.36 (m, 2H), 7.16 (m, 1H), 6.92 (m, 1H).

6-(2-(2,4-Difluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 455).LCMS: rt 2.26 min (A), MS (m/e) 335 MH⁺.

3-(3-(4-Aminoquinazolin-6-yl)pyridin-2-yl)phenol (Compound 456). LCMS:rt 2.16 min (A), MS (m/e) 315 MH⁺. ¹H NMR (DMSO-d₆, 300 MHz): 9.31 (s,1H), 8.68 (dd, J=4.8, 1.5 Hz, 1H), 8.37 (s, 1H), 8.28 (m, 1H), 7.90 (dd,J=7.8, 1.5 Hz, 1H), 7.74 (bs, 2H), 7.51 (dd, J=7.8, 4.5 Hz, 1H), 7.43(m, 1H), 7.31 (dd, J=8.7, 1.5 Hz, 1H), 7.00 (m, 1H), 6.77 (m, 1H),6.65-6.62 (m, 2H).

N-(3-(3-(4-Amino quinazolin-6-yl)pyridin-2-yl)phenyl)acetamide (Compound457). LCMS: rt 2.18 min (A), MS (m/e) 356 MH⁺.

6-(2-(3-Fluoro-5-methylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound458). LCMS: rt 2.45 min (A), MS (m/e) 331 MH⁺.

6-(2-(3-Fluoro-4-methylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound459). LCMS: rt 2.41 min (A), MS (m/e) 331 MH⁺.

6-(2-(3-Chloro-5-fluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound460). LCMS: rt 2.77 min (A), MS (m/e) 351 MH⁺.

6-(2-(3-Fluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 461).LCMS: rt 2.16 min (A), MS (m/e) 317 MH⁺. ¹H NMR (CD₃OD, 300 MHz): 8.68(dd, J=5.1, 1.8 Hz, 1H), 8.37 (s, 1H), 8.15 (m, 1H), 8.01 (dd, J=7.8,1.5 Hz, 1H), 7.59-7.54 (m, 2H), 7.48 (dd, J=8.4, 1.8 Hz, 1H), 7.22 (m,1H), 7.12 (m, 1H), 7.03 (m, 1H).

6-(2-(o-Tolyl)pyridin-3-yl)quinazolin-4-amine (Compound 462). LCMS: rt1.85 min (A), MS (m/e) 313 MH⁺.

6-(2-(5-Chloro-2-methylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound463). LCMS: rt 2.58 min (A), MS (m/e) 347 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.68 (dd, J=5.1, 1.8 Hz, 1H), 8.37 (s, 1H), 8.14 (m, 1H), 8.08 (dd,J=7.8, 1.8 Hz, 1H), 7.64 (dd, J=8.1, 5.1 Hz, 1H), 7.52-7.43 (m, 2H),7.28-7.21 (m, 2H), 7.11 (m, 1H), 1.90 (s, 3H).

6-(2-(3-Chloro-2-methylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound464). LCMS: rt 2.58 min (A), MS (m/e) 347 MH⁺.

6-(2-(6-Chloro-2-fluoro-3-methylphenyl)pyridin-3-yl)quinazolin-4-amine(Compound 465). LCMS: rt 2.97 min (A), MS (m/e) 365 MH⁺.

6-(2-(5-Fluoro-2-methylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound466). LCMS: rt 2.23 min (A), MS (m/e) 331 MH⁺.

6-(2-(4-Fluoro-2-methylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound467). LCMS: rt 2.07 min (A), MS (m/e) 331 MH⁺.

6-(2-(3-Fluoro-2-methylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound468). LCMS: rt 2.25 min (A), MS (m/e) 331 MH⁺.

6-(2-(3,4,5-Trifluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound469). LCMS: rt 2.74 min (A), MS (m/e) 353 MH⁺.

6-(2-(2,3-Dihydro-1H-inden-5-yl)pyridin-3-yl)quinazolin-4-amine(Compound 470). LCMS: rt 2.34 min (A), MS (m/e) 339 MH⁺.

5-(3-(4-Amino quinazolin-6-yl)pyridin-2-yl)-2,3-dihydro-1H-inden-1-one(Compound 471). LCMS: rt 2.09 min (A), MS (m/e) 353 MH⁺.

(E)-5-(3-(4-Aminoquinazolin-6-yl)pyridin-2-yl)-2,3-dihydro-1H-inden-1-one oxime (Compound472). LCMS: rt 2.15 min (A), MS (m/e) 367 MH⁺.

6-(2-(2-Fluoro-5-methoxyphenyl)pyridin-3-yl)quinazolin-4-amine (Compound473). LCMS: rt 2.32 min (A), MS (m/e) 347 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.69 (dd, J=5.1, 1.8 Hz, 1H), 8.40 (s, 1H), 8.16 (m, 1H), 8.02 (dd,J=7.8, 1.5 Hz, 1H), 7.62 (dd, J=7.8, 5.1 Hz, 1H), 7.54 (m, 2H), 7.03 (m,1H), 6.91-6.77 (m, 2H), 3.75 (s, 3H).

6-(2-(4-Fluoro-3-methoxyphenyl)pyridin-3-yl)quinazolin-4-amine (Compound474). LCMS: rt 2.14 min (A), MS (m/e) 347 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.68 (dd, J=4.8, 1.5 Hz, 1H), 8.43 (s, 1H), 8.20 (m, 1H), 8.02 (dd,J=7.8, 1.8 Hz, 1H), 7.60-7.51 (m, 3H), 7.08 (dd, J=8.1, 2.1 Hz, 1H),6.96 (dd, J=8.7, 11.1 Hz, 1H), 6.83-6.78 (m, 1H), 3.63 (s, 3H).

N-(3-(3-(4-Aminoquinazolin-6-yl)pyridin-2-yl)phenyl)-N′,N′-dimethylsulfonyldiamine(Compound 475). LCMS: rt 2.12 min (A), MS (m/e) 421 MH⁺.

6-(2-(4-Fluoro-3-(trifluoromethyl)phenyl)pyridin-3-yl)quinazolin-4-amine(Compound 476). LCMS: rt 3.13 min (A), MS (m/e) 385 MH⁺.

5-(3-(4-Amino quinazolin-6-yl)pyridin-2-yl)-2-fluorobenzonitrile(Compound 477). LCMS: rt 2.35 min (A), MS (m/e) 342 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.72 (dd, J=4.8, 1.5 Hz, 1H), 8.42 (s, 1H), 8.15 (m, 1H), 8.02(dd, J=6.0, 1.8 Hz, 1H), 7.64-7.51 (m, 4H), 7.21 (m, 1H).

6-(2-(3-Isopropylphenyl)pyridin-3-yl)quinazolin-4-amine (Compound 478).LCMS: rt 2.70 min (A), MS (m/e) 341 MH⁺.

6-(2-(3-(Benzyloxy)phenyl)pyridin-3-yl)quinazolin-4-amine (Compound479). LCMS: rt 3.20 min (A), MS (m/e) 405 MH⁺.

6-(2-(3-isopropoxyphenyl)pyridin-3-yl)quinazolin-4-amine (Compound 480).LCMS: rt 2.51 min (A), MS (m/e) 357 MH⁺.

2-(3-(3-(4-Amino quinazolin-6-yl)pyridin-2-yl)phenoxy)acetonitrile(Compound 481). LCMS: rt 2.09 min (A), MS (m/e) 354 MH⁺.

6-(2-(3-(2-Methoxyethoxy)phenyl)pyridin-3-yl)quinazolin-4-amine(Compound 482). LCMS: rt 2.09 min (A), MS (m/e) 373 MH⁺.

6-(2-(3-(Cyclopropylmethoxy)phenyl)pyridin-3-yl)quinazolin-4-amine(Compound 483). LCMS: rt 2.70 min (A), MS (m/e) 369 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.65 (dd, J=4.8, 1.5 Hz, 1H), 8.40 (s, 1H), 8.18 (m, 1H), 8.01(dd, J=7.8, 1.5 Hz, 1H), 7.57-7.51 (m, 2H), 7.46 (dd, J=9.0, 2.1 Hz,1H), 7.17 (m, 1H), 6.92-6.89 (m, 1H), 6.85-6.78 (m, 2H), 3.53 (d, J=7.2Hz, 2H), 0.93 (m, 1H), 0.43 (m, 2H), 0.13 (m, 2H).

6-(2-(3-(2,2,2-Trifluoroethoxy)phenyl)pyridin-3-yl)quinazolin-4-amine(Compound 484). LCMS: rt 3.59 min (A), MS (m/e) 387 MH⁺. ¹H NMR (CD₃OD,300 MHz): 8.69 (dd, J=4.8, 1.5 Hz, 1H), 8.42 (s, 1H), 8.18 (m, 1H), 8.02(dd, J=7.8, 1.5 Hz, 1H), 7.59-7.53 (m, 3H), 7.19 (m, 1H), 7.03 (m, 1H),6.97-6.90 (m, 2H), 3.53 (q, J=7.8 Hz, 2H).

6-(2-(3-Morpholinophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 485).LCMS: rt 2.66 min (A), MS (m/e) 384 MH⁺.

7-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazoline-2,4-diamine(Compound 486). LCMS: rt 2.96 min (A), MS (m/e) 366 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinazoline-2,4-diamine(Compound 487). LCMS: rt 2.53 min (A), MS (m/e) 346 MH⁺.

7-(2-(3-Chlorophenyl)pyridin-3-yl)quinazoline-2,4-diamine (Compound488). LCMS: rt 2.77 min (A), MS (m/e) 348 MH⁺.

7-(2-(m-Tolyl)pyridin-3-yl)quinazoline-2,4-diamine (Compound 489). LCMS:rt 2.89 min (B), MS (m/e) 328 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N-(pyridin-3-yl)quinazolin-4-amine(Compound 490). LCMS: rt 3.85 min (A), MS (m/e) 428 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N-(6-methylpyridin-3-yl)quinazolin-4-amine(Compound 491). LCMS: rt 3.54 min (A), MS (m/e) 442 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N-(pyridin-4-yl)quinazolin-4-amine(Compound 492). LCMS: rt 3.42 min (A), MS (m/e) 428 MH⁺.

3-(3-(4-Amino quinazolin-6-yl)pyridin-2-yl)-5-chlorophenol (Compound493). LCMS: rt 2.32 min (A), MS (m/e) 349 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.66 (dd, J=4.8, 1.5 Hz, 1H), 8.42 (s, 1H), 8.21 (m, 1H), 8.03 (dd,J=7.8, 1.5 Hz, 1H), 7.61-7.49 (m, 3H), 6.83 (m, 1H), 6.73 (m, 1H), 6.60(m, 1H).

3-(3-(4-Aminoquinazolin-6-yl)pyridin-2-yl)-5-fluorophenol (Compound494). LCMS: rt 1.94 min (A), MS (m/e) 333 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.65 (dd, J=4.8, 1.5 Hz, 1H), 8.41 (s, 1H), 8.12 (m, 1H), 7.95 (dd,J=7.8, 1.5 Hz, 1H), 7.60-7.45 (m, 3H), 6.58 (m, 1H), 6.53-6.46 (m, 2H).

3-(3-(4-Aminoquinazolin-6-yl)pyridin-2-yl)-5-methylphenol (Compound495). LCMS: rt 1.69 min (A), MS (m/e) 329 MH⁺. ¹H NMR (CD₃OD, 300 MHz):8.63 (dd, J=4.8, 1.5 Hz, 1H), 8.44 (s, 1H), 8.23 (m, 1H), 8.16 (m, 1H),8.01 (dd, J=7.8, 1.5 Hz, 1H), 7.56-7.51 (m, 3H), 6.65 (m, 1H), 6.56 (m,1H), 6.47 (m, 1H), 2.15 (s, 3H).

7-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazolin-2-amine (Compound496). LCMS: rt 2.36 min (A), MS (m/e) 351 MH⁺. ¹H NMR (CD₃OD, 300 MHz):9.06 (bs, 1H), 8.68 (dd, J=4.8, 1.5 Hz, 1H), 7.99 (dd, J=7.8, 1.5 Hz,1H), 7.75 (d, J=8.1 Hz, 1H), 7.57 (dd, J=7.8, 4.8 Hz, 1H), 7.53 (m, 1H),7.36 (m, 1H), 7.22-7.17 (m, 1H), 7.11-7.05 (m, 2H).

6-(2-(2-Chlorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 497).LCMS: rt 2.29 min (A), MS (m/e) 333 MH⁺.

6-(2-(2,3-Dichlorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 498).LCMS: rt 2.78 min (A), MS (m/e) 368 MH⁺.

6-(2-(2-Chloro-4-fluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound499). LCMS: rt 2.48 min (A), MS (m/e) 351 MH⁺.

6-(2-(2,4-Dichlorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 500).LCMS: rt 3.63 min (B), MS (m/e) 368 MH⁺.

6-(2-(2,5-Dichlorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound 501).LCMS: rt 3.55 min (B), MS (m/e) 368 MH⁺. ¹H NMR (CD₃OD, 300 MHz): 8.69(dd, J=5.1, 1.5 Hz, 1H), 8.36 (s, 1H), 8.13 (m, 1H), 8.07 (dd, J=7.8,1.5 Hz, 1H), 7.66 (dd, J=7.8, 5.1 Hz, 1H), 7.56-7.53 (m, 3H), 7.33 (m,1H), 6.26 (m, 1H).

6-(2-(2,4-Difluoro-5-methoxyphenyl)pyridin-3-yl)quinazolin-4-amine(Compound 502). LCMS: rt 3.21 min (B), MS (m/e) 365 MH⁺.

6-(2-(2-Chloro-3-fluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound503). LCMS: rt 3.27 min (B), MS (m/e) 351 MH⁺.

6-(2-(2-Chloro-5-fluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound504). LCMS: rt 3.23 min (B), MS (m/e) 351 MH⁺.

6-(2-(2,4-Dichloro-5-fluorophenyl)pyridin-3-yl)quinazolin-4-amine(Compound 505). LCMS: rt 3.79 min (B), MS (m/e) 386 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinazoline (Compound 506).LCMS: rt 5.24 min (A), MS (m/e) 336 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-4-cyclopropylquinazoline(Compound 507). LCMS: rt 7.15 min (A), MS (m/e) 376 MH⁺.

2-(2-Fluorophenyl)-3,4′-bipyridine (Compound 508). ¹H NMR (300 MHz,DMSO-d₆): δ 8.74 (dd, J=4.8, 1.7 Hz, 1H), 8.45 (dd, J=4.4, 1.7 Hz, 2H),7.94 (dd, J=1.7, 7.8 Hz, 1H), 7.58 (dd, J=7.8, 4.8 Hz, 1H), 7.58 (dd,J=7.8, 4.8 Hz, 1H), 7.47 (td, J=7.5, 1.8 Hz, 1H), 7.44-7.34 (m, 1H),7.23 (td, J=7.5, 1.1 Hz, 1H), 7.15 (dd, J=4.4, 1.7 Hz, 2H), 7.08-7.00(m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −115.75 (ddd, J=10.4, 7.5, 5.4Hz). LCMS: rt 4.35 min (A), purity 99%, MS (m/e) 251 (MH⁺).

5-(Benzo[d]thiazol-6-yl)-6-(4-fluoro-3-methylphenyl)-N-(pyridin-4-ylmethyl)pyridin-3-amine(Compound 509). LCMS: rt 4.46 min (A), MS (m/e) 427 MH⁺.

4-(2-(2-Fluorophenyl)pyridin-3-yl)quinolone (Compound 510). LCMS: rt4.08min (B), purity 99%, MS (m/e) 301 (MH⁺).

4-(2-(3,4-Difluorophenyl)pyridin-3-yl)quinolone (Compound 511). LCMS:rt4.82 min (B), purity 99%, MS (m/e) 319 (MH⁺).

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinoline (Compound 512).LCMS: rt 4.73 min (B), purity 99%, MS (m/e) 315 (MH⁺).

4-(2-(3-Fluorophenyl)pyridin-3-yl)quinolone (Compound 513). LCMS: rt4.46 min (B), purity 99%, MS (m/e) 301 (MH⁺).

4-(2-(4-Fluorophenyl)pyridin-3-yl)quinoline (Compound 514). LCMS: rt4.34min (B), purity 99%, MS (m/e) 301 (MH⁺).

4-(2-(m-Tolyl)pyridin-3-yl)quinoline (Compound 515). LCMS: rt 4.32 min(B), purity 99%, MS (m/e) 297 (MH⁺).

4-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)quinolone (Compound 516).LCMS: rt 6.04 min (B), purity 99%, MS (m/e) 315 (MH⁺).

5-(6-Methyl-[2,3′-bipyridin]-2′-yl)-1H-indazole (Compound 517). ¹H NMR(300 MHz, DMSO-d₆): δ 12.97 (s, 1H), 8.63 (dd, J=4.7, 1.7 Hz, 1H), 7.92(dd, J=9.7, 1.7 Hz, 1H), 7.64 (s, 1H), 7.40 (dd, J=8.0, 4.5 Hz, 2H),7.37-7.29 (m, 2H), 7.16 (dd, J=8.7, 1.5 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H),6.73 (d, J=7.8 Hz, 1H), 2.41 (s, 3H). LCMS: rt 2.34 min (B), purity 99%,MS (m/e) 287 (MH⁺).

2′-(Benzo[d][1,3]dioxol-5-yl)-6-methyl-2,3′-bipyridine (Compound 518).LCMS: rt 2.82 min (B), purity 99%, MS (m/e) 291 (MH⁺).

6-(6-Methyl-[2,3′-bipyridin]-2′-yl)quinoxaline (Compound 519). LCMS: rt2.80 min (B), purity 99%, MS (m/e) 299 (MH⁺).

5-(6-Methyl-[2,3′-bipyridin]-2′-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one(Compound 520). LCMS: rt 2.01 min (B), purity 99%, MS (m/e) 303 (MH⁺).

6-(6-Methyl-[2,3′-bipyridin]-2′-yl)-1H-benzo[d]imidazole (Compound 521).¹H NMR (300 MHz, DMSO-d₆): δ 12.1 (br s, 1H), 8.68 (dd, J=4.7, 1.7 Hz,1H), 8.16 (s, 1H), 7.96 (dd, J=7.8, 1.7 Hz, 1H), 7.50-7.37 (ddd, J=15.4,14.4, 8.8 Hz, 4H), 7.10 (d, J=7.7 Hz, 2H), 6.76 (d, J=7.7 Hz, 1H), 2.47(s, 3H). LCMS: rt 1.23 min (B), purity 99%, MS (m/e) 287 (MH⁺).

6-(6-Methyl-[2,3′-bipyridin]-2′-yl)isoquinoline (Compound 522). LCMS: rt1.93 min (B), purity 99%, MS (m/e) 298 (MH⁺).

2-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1,6-naphthyridine (Compound523). ¹H NMR (300 MHz, DMSO-d₆): δ 9.35 (d, J=0.9 Hz, 1H), 8.78 (dd,J=4.7, 1.7 Hz, 1H), 8.74 (d, J=5.9 Hz, 1H), 8.38 (dd, J=8.6, 0.9 Hz,1H), 8.14 (dd, J=7.8, 1.7 Hz, 1H), 7.91 (d, J=5.9 Hz, 1H), 7.57 (dd,J=7.8, 4.7 Hz, 1H), 7.38 (dd, J=7.6, 1.9 Hz, 1H), 7.30 (d, J=8.5 Hz,1H), 7.01-6.86 (m, 2H), 2.13 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−117.88 (d, J=8.1 Hz). LCMS: rt 4.58 min (A), purity 99%, MS (m/e) 316(MH⁺).

2-(2-(m-Tolyl)pyridin-3-yl)-1,6-naphthyridine (Compound 524). ¹H NMR(300 MHz, DMSO-d₆): δ 9.33 (s, 1H), 8.74 (d, J=5.9 Hz, 2H), 8.33 (d,J=8.6 Hz, 1H), 8.14 (d, J=7.7 Hz, 1H), 7.91 (d, J=5.9 Hz, 1H), 7.56 (dd,J=7.7, 4.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.08 (d, J=7.6 Hz, 2H), 6.93(d, J=6.8 Hz, 1H), 2.18 (s, 3H). LCMS: rt 4.11 min (A), purity 99%, MS(m/e) 298 (MH⁺).

2-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-1,6-naphthyridine (Compound525). LCMS: rt 4.71 min (A), purity 99%, MS (m/e) 324 (MH⁺).

2′-(4-Fluoro-3-methylphenyl)[3,3′-bipyridin]-6-amine (Compound 526). ¹HNMR (300 MHz, DMSO-d₆): δ 8.60 (dd, J=4.7, 1.6 Hz, 1H), 7.85-7.73 (m,2H), 7.42 (dd, J=7.8, 4.7 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.24 (dd,J=8.8, 2.4 Hz, 1H), 7.13-6.95 (m, 2H), 6.66 (br s, 2H), 6.51 (d, J=8.8Hz, 1H), 2.19 (d, J=1.5 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.73(s). LCMS: rt 1.76 min (A), purity 99%, MS (m/e) 280 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-methylimidazo[1,2-a]pyridine(Compound 527). ¹H NMR (300 MHz, DMSO-d₆): δ 8.68 (dd, J=4.7, 1.7 Hz,1H), 8.28 (dd, J=1.7, 0.9 Hz, 1H), 7.98 (dd, J=7.8, 1.7 Hz, 1H), 7.49(dd, J=7.8, 4.8 Hz, 1H), 7.45 (app dd, J=8.6 and 0.9 Hz, 1H), 7.38 (d,J=0.9 Hz, 1H), 7.36 (dd, J=8.6, 0.9 Hz, 1H), 7.09-7.05 (m, 1H), 6.97(dd, J=9.6, 8.6 Hz, 1H), 6.77 (dd, J=9.3, 1.8 Hz, 1H), 2.43 (s, 3H),2.16 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.43 (ddd, J=10.0, 7.5,3.8 Hz). LCMS: rt 3.83 min (A), purity 99%, MS (m/e) 318 (MH⁺).

3-Methyl-6-(2-(m-Tolyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound528). LCMS: rt 3.40 min (A), purity 99%, MS (m/e) 300 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-3-methylimidazo[1,2-a]pyridine(Compound 529). LCMS: rt 3.98 min (A), purity 99%, MS (m/e) 326 (MH⁺).

3-Methyl-6-(2-(3-(trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 530). LCMS: rt 4.90 min (A), purity 99%, MS (m/e) 354 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-2-methylimidazo[1,2-a]pyridine(Compound 531). LCMS: rt 3.86 min (A), purity 99%, MS (m/e) 318 (MH⁺).

2-Methyl-6-(2-(m-tolyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound532). ¹H NMR (300 MHz, DMSO-d₆): δ 8.67 (dd, J=4.7, 1.7 Hz, 1H), 8.43(dd, J=1.8, 1.0 Hz, 1H), 7.88 (dd, J=7.7, 1.7 Hz, 1H), 7.61 (s, 1H),7.46 (dd, J=7.8, 4.7 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.25 (d, J=9.3 Hz,1H), 7.10-7.08 (app m, 2H), 7.06-7.00 (m, 1H), 6.75 (dd, J=9.3, 1.8 Hz,1H), 2.30 (s, 3H), 2.22 (s, 3H). LCMS: rt 3.41 min (A), purity 99%, MS(m/e) 300 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-2-methylimidazo[1,2-a]pyridine(Compound 533). LCMS: rt 3.96 min (A), purity 99%, MS (m/e) 326 (MH⁺).

2-Methyl-6-(2-(3-trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 534). LCMS: rt 4.86 min (A), purity 99%, MS (m/e) 354 (MH⁺).

2-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1,5-naphthyridine (Compound535). ¹H NMR (300 MHz, DMSO-d₆): δ 9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.80(dd, J=4.8, 1.6 Hz, 1H), 8.44 (dd, J=8.9, 1.1 Hz, 1H), 8.35-8.17 (m,2H), 7.81 (dd, J=8.5, 4.2 Hz, 1H), 7.63 (dd, J=7.8, 4.9 Hz, 1H), 7.40(d, J=8.7 Hz, 2H), 6.96 (d, J=7.9 Hz, 2H), 2.28-1.96 (m, 3H). ¹⁹F NMR(282 MHz, DMSO-d₆): δ −117.43 (dd, J=13.7, 6.5 Hz), −117.43 (dd, J=13.7,6.5 Hz). LCMS: rt5.20 min (A), purity 99%, MS (m/e) 316 (MH⁺).

2-(2-(m-Tolyl)pyridin-3-yl)-1,5-naphthyridine (Compound 536). LCMS:rt4.78 min (A), purity 99%, MS (m/e) 298 (MH⁺).

2-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-1,5-naphthyridine (Compound537). LCMS: rt5.30 min (A), purity 99%, MS (m/e) 324 (MH⁺).

2-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)-1,5-naphthyridine(Compound 538). LCMS: rt 5.43 min (A), purity 99%, MS (m/e) 352 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinoxaline (Compound 539).LCMS: rt5.25 min (A), purity 99%, MS (m/e) 316 (MH⁺).

6-(2-(m-Tolyl)pyridin-3-yl)quinoxaline (Compound 540). ¹H NMR (300 MHz,DMSO-d₆): δ 8.93 (s, 2H), 8.78 (dd, J=4.9, 1.6 Hz, 1H), 8.17 (dd, J=7.8,1.6 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.66 (dd,J=7.8, 5.0 Hz, 1H), 7.53 (dd, J=8.7, 2.0 Hz, 1H), 7.31 (d, J=0.5 Hz,1H), 7.16-7.03 (m, 2H), 6.98 (d, J=7.2 Hz, 1H), 2.19 (s, 3H). LCMS: rt4.86 min (A), purity 99%, MS (m/e) 298 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)quinoxaline (Compound 541). LCMS:rt5.35 min (A), purity 99%, MS (m/e) 324 (MH⁺).

6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)quinoxaline (Compound 542).LCMS: rt6.61 min (A), purity 99%, MS (m/e) 351 (MH⁺).

4-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)morpholine(Compound 543). ¹H NMR (300 MHz, DMSO-d₆): δ 8.67 (dd, J=4.7, 1.7 Hz,1H), 7.98 (dd, J=7.8, 1.7 Hz, 1H), 7.90 (dd, J=1.7, 1.0 Hz, 1H), 7.50(dd, J=7.8, 4.7 Hz, 1H), 7.47-7.39 (m, 2H), 7.26 (s, 1H), 7.11-7.04 (m,1H), 7.00 (d, J=9.6 Hz, 1H), 6.98-6.92 (m, 1H), 3.68 (dd, J=5.5, 3.7 Hz,4H), 2.81 (dd, J=5.5, 3.7 Hz, 4H), 2.17 (d, J=1.6 Hz, 3H). ¹⁹F NMR (282MHz, DMSO-d₆): δ −118.33-−118.66 (m). LCMS: rt4.25 min (A), purity 99%,MS (m/e) 389 (MH⁺).

4-(6-(2-(m-Tolyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)morpholine(Compound 544). LCMS: rt3.85 min (A), purity 99%, MS (m/e) 371 (MH⁺).

4-(6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)morpholine(Compound 545). LCMS: rt4.33 min (A), purity 99%, MS (m/e) 397 (MH⁺).

4-(6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)morpholine(Compound 546). LCMS: rt5.15 min (A), purity 99%, MS (m/e) 425 (MH⁺).

4-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinolin-4-yl)morpholine(Compound 547). LCMS: rt4.15 min (A), purity 99%, MS (m/e) 400 (MH⁺).

4-(6-(2-(m-Tolyl)pyridin-3-yl)quinolin-4-yl)morpholine (Compound 548).¹H NMR (300 MHz, DMSO-d₆): δ 8.69 (dd, J=4.7, 1.7 Hz, 1H), 8.65 (d,J=5.0 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.92 (dd, J=7.8, 1.7 Hz, 1H),7.75 (dd, J=8.6, 2.0 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.50 (dd, J=7.8,4.7 Hz, 1H), 7.31 (s, 1H), 7.09-6.99 (m, 2H), 6.99-6.94 (app m, 1H),6.91 (d, J=5.1 Hz, 1H), 3.75-3.41 (m, 4H), 2.89-2.62 (m, 4H), 2.19 (s,3H). LCMS: rt3.81 min (A), purity 99%, MS (m/e) 381 (MH⁺).

4-(6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)quinolin-4-yl)morpholine(Compound 549). LCMS: rt4.20 min (A), purity 99%, MS (m/e) 408 (MH⁺).

4-(6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)quinolin-4-yl)morpholine(Compound 550). LCMS: rt5.11 min (A), purity 99%, MS (m/e) 436 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethylimidazo[1,2-a]pyridin-3-amine(Compound 551). LCMS: rt4.33 min (A), purity 99%, MS (m/e) 347 (MH⁺).

N,N-Dimethyl-6-(2-(m-tolyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-amine(Compound 552). LCMS: rt3.93 min (A), purity 99%, MS (m/e) 329 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-N,N-dimethylimidazo[1,2-a]pyridin-3-amine(Compound 553). LCMS: rt4.45 min (A), purity 99%, MS (m/e) 355 (MH⁺).

N,N-Dimethyl-6-(2-(3-(trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-amine(Compound 554). LCMS: rt5.33 min (A), purity 99%, MS (m/e) 383 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine(Compound 555). ¹H NMR (300 MHz, DMSO-d₆): δ 8.71 (dd, J=4.8, 1.6 Hz,1H), 8.29 (s, 1H), 8.17 (d, J=1.0 Hz, 1H), 7.99 (dd, J=7.8, 1.7 Hz, 1H),7.71 (dd, J=9.4, 0.8 Hz, 1H), 7.52 (dd, J=7.8, 4.8 Hz, 1H), 7.42 (dd,J=7.7, 1.6 Hz, 1H), 7.24 (dd, J=9.4, 1.7 Hz, 1H), 7.06 (ddd, J=7.6, 5.3,2.3 Hz, 1H), 7.02-6.93 (m, 1H), 2.16 (d, J=1.7 Hz, 3H). ¹⁹F NMR (282MHz, DMSO-d₆): δ −60.01 (s), −118.29 (d, J=5.5 Hz). LCMS: rt5.90 min(A), purity 99%, MS (m/e) 372 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine(Compound 556). LCMS: rt5.90 min (A), purity 99%, MS (m/e) 380 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 557). LCMS: rt5.38 min (A), purity 99%, MS (m/e) 329 (MH⁺).

6-(2-(m-Tolyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 558). ¹H NMR (300 MHz, DMSO-d₆): δ 8.72 (dd, J=4.8, 1.7 Hz,1H), 8.62 (d, J=0.6 Hz, 1H), 8.44 (s, 1H), 8.05 (dd, J=7.8, 1.6 Hz, 1H),7.64 (d, J=9.3 Hz, 1H), 7.52 (dd, J=7.8, 4.8 Hz, 1H), 7.34 (s, 1H),7.16-7.02 (m, 4H), 2.24 (s, 3H). LCMS: rt4.93 min (A), purity 99%, MS(m/e) 311 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 559). LCMS: rt5.48 min (A), purity 99%, MS (m/e) 337 (MH⁺).

6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 560). LCMS: rt6.66 min (A), purity 99%, MS (m/e) 365 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine(Compound 561). LCMS: rt4.90 min (A), purity 99%, MS (m/e) 373 (MH⁺).

3-(Pyrrolidin-1-yl)-6-(2-(m-tolyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 562). LCMS: rt4.46 min (A), purity 99%, MS (m/e) 355 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-3-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine(Compound 563). LCMS: rt4.93 min (A), purity 99%, MS (m/e) 381 (MH⁺).

3-(Pyrrolidin-1-yl)-6-(2-(3-(trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 564). ¹H NMR (300 MHz, DMSO-d₆): δ 8.73 (dd, J=4.7, 1.6 Hz,1H), 8.02 (dd, J=7.8, 1.6 Hz, 1H), 7.96-7.87 (m, 1H), 7.81 (s, 1H), 7.63(d, J=7.7 Hz, 1H), 7.56 (dt, J=7.8, 3.7 Hz, 2H), 7.47 (t, J=7.7 Hz, 1H),7.38 (dd, J=9.3, 0.8 Hz, 1H), 7.15 (s, 1H), 6.91 (dd, J=9.3, 1.8 Hz,1H), 2.93 (t, J=6.5 Hz, 4H), 1.96-1.52 (m, 4H). ¹⁹F NMR (282 MHz,DMSO-d₆): δ −61.36 (s). LCMS: rt5.78 min (A), purity 99%, MS (m/e) 409(MH⁺).

(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methanol(Compound 565). ¹H NMR (300 MHz, DMSO-d₆): δ 8.69 (dd, J=4.7, 1.6 Hz,1H), 8.46 (s, 1H), 7.96 (dd, J=7.7, 1.6 Hz, 1H), 7.54 (s, 1H), 7.53-7.48(m, 1H), 7.44 (t, J=8.6 Hz, 2H), 7.11-7.02 (m, 1H), 6.98 (t, J=9.1 Hz,1H), 6.84 (dd, J=9.3, 1.6 Hz, 1H), 5.26 (s, 1H), 4.78 (s, 2H), 2.17 (s,3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.29 (s). LCMS: rt3.36 min (A),purity 99%, MS (m/e) 334 (MH⁺).

(6-(2-(m-Tolyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methanol(Compound 566). LCMS: rt2.55 min (A), purity 99%, MS (m/e) 316 (MH⁺).

(6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methanol(Compound 567). LCMS: rt3.53 min (A), purity 99%, MS (m/e) 342 (MH⁺).

(6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methanol(Compound 568). LCMS: rt4.38 min (A), purity 99%, MS (m/e) 370 (MH⁺).

4-((6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine(Compound 569). ¹H NMR (300 MHz, DMSO-d₆): δ 8.69 (dd, J=4.7, 1.7 Hz,1H), 8.33 (dd, J=1.7, 0.9 Hz, 1H), 7.90 (dd, J=7.8, 1.7 Hz, 1H),7.55-7.46 (m, 3H), 7.43 (dd, J=7.6, 1.6 Hz, 1H), 7.12-7.04 (m, 1H),7.04-6.93 (m, 2H), 3.72 (s, 2H), 3.49-3.36 (m, 4H), 2.33-2.18 (m, 4H),2.14 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.39 (s, 1H). LCMS:rt3.38 min (A), purity 99%, MS (m/e) 403 (MH⁺).

4-((6-(2-(m-Tolyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine(Compound 570). LCMS: rt2.65 min (A), purity 99%, MS (m/e) 385 (MH⁺).

4-((6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine(Compound 571). LCMS: rt3.53 min (A), purity 99%, MS (m/e) 411 (MH⁺).

4-(6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine(Compound 572). LCMS: rt4.15 min (A), purity 99%, MS (m/e) 439 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 573). ¹H NMR (300 MHz, DMSO-d₆): δ 10.25 (s, 1H), 9.54 (s,1H), 8.75 (dd, J=4.8, 1.6 Hz, 1H), 8.67 (s, 1H), 8.05 (dd, J=7.8, 1.6Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.59 (dd, J=7.8, 4.8 Hz, 1H), 7.47 (dd,J=7.5, 1.6 Hz, 1H), 7.20 (dd, J=9.3, 1.8 Hz, 1H), 7.16 (s, 2H),7.14-7.06 (m, 1H) 6.93 (m, J=9.1 Hz, 1H), 3.77 (s, 6H), 3.63 (s, 3H),2.17 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.82 (s, 1H). LCMS:rt5.53 min (A), purity 99%, MS (m/e) 513 (MH⁺).

6-(2-(m-Tolyl)pyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 574). LCMS: rt5.18 min (A), purity 99%, MS (m/e) 495 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 575). LCMS: rt5.55 min (A), purity 99%, MS (m/e) 521 (MH⁺).

6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 576). LCMS: rt 6.26 min (A), purity 99%, MS (m/e) 549 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine(Compound 577). ¹H NMR (300 MHz, DMSO-d₆): δ 8.69 (dd, J=4.7, 1.5 Hz,1H), 8.61 (s, 1H), 8.04 (d, J=9.3, 1.6 Hz, 1H), 8.01 (s, 1H), 7.68 (d,J=9.3 Hz, 1H), 7.56-7.39 (m, 2H), 7.17 (d, J=9.4 Hz, 1H), 7.09 (ddd,J=7.6, 5.1, 2.3 Hz, 1H), 7.01-6.87 (app m, 3H), 3.82 (s, 6H), 3.76-3.67(m, 3H), 2.17 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.31 (s, 1H).LCMS: rt5.05 min (A), purity 99%, MS (m/e) 470 (MH⁺).6-(2-(m-Tolyl)pyridin-3-yl)-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine(Compound 578). LCMS: rt4.68 min (A), purity 99%, MS (m/e) 452 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylicacid (Compound 579). ¹H NMR (300 MHz, DMSO-d₆) δ 13.01 (br s, 1H), 9.21(dd, J=1.9, 1.0 Hz, 1H), 8.71 (dd, J=4.8, 1.7 Hz, 1H), 8.23 (s, 1H),7.97 (dd, J=7.8, 1.7 Hz, 1H), 7.65 (dd, J=9.3, 1.0 Hz, 1H), 7.52 (dd,J=7.7, 4.8 Hz, 1H), 7.43 (dd, J=7.7, 2.3 Hz, 1H), 7.14 (dd, J=9.3, 1.9Hz, 1H), 7.06 (ddd, J=7.8, 5.1, 2.3 Hz, 1H), 6.96 (dd, J=9.7, 8.4 Hz,1H), 2.16 (s, 3H). LCMS: rt3.70 min (A), purity 99%, MS (m/e) 348 (MH⁺).

(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)(morpholino)methanone(Compound 580). ¹H NMR (300 MHz, DMSO-d₆): δ 8.89-8.83 (app m, 1H), 8.70(dd, J=4.8, 1.2 Hz, 1H), 8.03 (d, J=0.5 Hz, 1H), 7.94 (dd, J=7.8, 1.2Hz, 1H), 7.57 (d, J=9.3 Hz, 1H), 7.51 (dd, J=7.6, 5.0 Hz, 1H), 7.44 (d,J=7.8 Hz, 1H), 7.13-7.04 (m, 1H), 7.02-6.95 (m, 2H), 3.71-3.69 (m, 4H),3.65-3.62 (m, 4H), 2.17 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.29(s, 1H). LCMS: rt 4.58 min (A), purity 99%, MS (m/e) 417 (MH⁺).

(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)(4-methylpiperazin-1-yl)methanone(Compound 581). LCMS: rt3.41 min (A), purity 99%, MS (m/e) 430 (MH⁺).

N-(3,4-Dimethoxyphenyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 582). ¹H NMR (300 MHz, DMSO-d₆): δ 10.32 (s, 1H), 9.58 (dd,J=1.7, 0.9 Hz, 1H), 8.77 (dd, J=4.9, 1.6 Hz, 1H), 8.73 (s, 1H), 8.07(dd, J=7.8, 1.6 Hz, 1H), 7.76 (dd, J=9.3, 0.9 Hz, 1H), 7.61 (dd, J=7.8,4.9 Hz, 1H), 7.47 (dd, J=7.5, 1.5 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.28(ddd, J=10.3, 9.1, 2.1 Hz, 2H), 7.10 (dd, J=5.2, 2.5 Hz, 1H), 6.97 (dd,J=17.6, 9.1 Hz, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 2.17 (s, 3H). ¹⁹F NMR(282 MHz, DMSO-d₆): δ −118.32 (s, 1H). LCMS: rt5.23 min (A), purity 99%,MS (m/e) 483 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-propylimidazo[1,2-a]pyridine-3-carboxamide(Compound 583). LCMS: rt4.51 min (B), purity 99%, MS (m/e) 389 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide(Compound 584). ¹H NMR (300 MHz, DMSO-d₆): δ 9.48 (s, 1H), 8.71 (dd,J=4.8, 1.6 Hz, 1H), 8.48 (app qt, J=4.7 Hz, 1H), 8.26 (s, 1H), 7.93 (dd,J=7.8, 1.7 Hz, 1H), 7.55 (d, J=9.3 Hz, 1H), 7.51 (dd, J=7.8, 4.7 Hz,1H), 7.42 (d, J=5.4 Hz, 1H), 7.11-7.04 (m, 1H), 7.04-6.91 (m, 2H), 2.79(d, J=4.6 Hz, 3H), 2.15 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.32(s, 1H). LCMS: rt3.57 min (B), purity 99%, MS (m/e) 361 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 585). LCMS: rt2.42 min (B), purity 99%, MS (m/e) 460 (MH⁺).

1-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one(Compound 586). LCMS: rt4.68 min (A), purity 99%, MS (m/e) 346 (MH⁺).

1-(6-(2-(m-Tolyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one(Compound 587). LCMS: rt4.26 min (A), purity 99%, MS (m/e) 328 (MH⁺).

1-(6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one(Compound 588). ¹H NMR (300 MHz, DMSO-d₆): δ 9.44 (dd, J=1.7, 0.8 Hz,1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 8.60 (s, 1H), 7.94 (dd, J=7.7, 1.7Hz, 1H), 7.69 (dd, J=9.2, 0.7 Hz, 1H), 7.51 (dd, J=7.7, 4.8 Hz, 1H),7.23 (dd, J=9.2, 1.8 Hz, 1H), 7.16-7.04 (m, 2H), 7.03-6.96 (m, 2H), 2.53(s, 3H), 1.87-1.66 (m, 1H), 0.89-0.66 (m, 2H), 0.44-0.20 (m, 2H). LCMS:rt 4.81 min (A), purity 99%, MS (m/e) 354 (MH⁺).

1-(6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one(Compound 589). LCMS: rt 5.71 min (A), purity 99%, MS (m/e) 382 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 590). LCMS: rt2.89 min (B), purity 99%, MS (m/e) 473 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 591). LCMS: rt 2.76 min (B), purity 99%, MS (m/e) 487 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 592). ¹H NMR (300 MHz, DMSO-d₆): δ 9.54 (dd, J=1.8, 0.9 Hz,1H), 8.78 (dd, J=4.8, 1.7 Hz, 1H), 8.43 (s, 1H), 8.34 (d, J=7.6 Hz, 1H),8.01 (dd, J=7.8, 1.7 Hz, 1H), 7.69-7.54 (m, 2H), 7.50 (dd, J=7.6, 2.0Hz, 1H), 7.19-6.99 (m, 3H), 3.95-3.70 (m, 1H), 2.85 (d, J=11.7 Hz, 2H),2.24 (s, 6H), 2.01 (t, J=10.7 Hz, 2H), 1.85 (d, J=9.3 Hz, 2H), 1.76-1.51(m, 2H). LCMS: rt 3.03 min (B), purity 99%, MS (m/e) 444 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 593). LCMS: rt 4.78 min (B), purity 99%, MS (m/e) 431 (MH⁺).

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine(Compound 594). ¹H NMR (300 MHz, DMSO-d₆): δ 8.65 (dd, J=4.7, 1.6 Hz,1H), 8.31 (s, 1H), 8.17 (dd, J=7.3, 0.9 Hz, 1H), 7.89 (dd, J=7.6, 1.4Hz, 1H), 7.55 (s, 1H), 7.46 (dd, J=7.3, 4.7 Hz, 2H), 7.36 (s, 1H), 7.11(ddd, J=7.8, 5.0, 2.5 Hz, 1H), 7.06-6.94 (m, 1H), 6.20 (d, J=7.3 Hz,1H), 2.18 (s, 4H). LCMS: rt3.53 min (A), purity 99%, MS (m/e) 304 (MH⁺).

7-(2-(m-Tolyl)pyridin-3-yl)imidazo[1,5-a]pyridine (Compound 595). LCMS:rt3.01 min (A), purity 99%, MS (m/e) 286 (MH⁺).

7-(2-(3-Cyclopropylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine (Compound596). LCMS: rt3.73 min (A), purity 99%, MS (m/e) 312 (MH⁺).

7-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,5-a]pyridine(Compound 597). LCMS: rt4.66 min (A), purity 99%, MS (m/e) 340 (MH⁺).

rac-1-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-ol(Compound 598). ¹H NMR (300 MHz, DMSO-d₆): δ 8.69 (dd, J=4.7, 1.7 Hz,1H), 8.40 (d, J=0.9 Hz, 1H), 7.95 (dd, J=7.8, 1.7 Hz, 1H), 7.51 (dd,J=7.8, 4.8 Hz, 1H), 7.47-7.37 (m, 3H), 7.12-7.02 (m, 1H), 6.98 (t, J=9.1Hz, 1H), 6.86 (dd, J=9.3, 1.8 Hz, 1H), 5.33 (br s, 1H), 5.07 (app qt,J=6.5 Hz, 1H), 2.14 (s, 3H), 1.50 (d, J=6.5 Hz, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆): δ −118.42 (s). LCMS: rt3.78 min (A), purity 99%, MS (m/e) 348(MH⁺).

2-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)propan-2-ol(Compound 599). LCMS: rt 4.03 min (A), purity 99%, MS (m/e) 362 (MH⁺).

6-(2-(3-(Methyl-d₃)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound600). LCMS: rt3.35 min (A), purity 99%, MS (m/e) 289 (MH⁺).

6-(2-(3-(Methyl-d₃)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 601). ¹H NMR (300 MHz, DMSO-d₆): δ 8.72 (dd, J=4.8, 1.7 Hz,1H), 8.62 (dd, J=1.7, 1.0 Hz, 1H), 8.44 (s, 1H), 8.05 (dd, J=7.8, 1.7Hz, 1H), 7.64 (dd, J=9.3, 0.9 Hz, 1H), 7.52 (dd, J=7.8, 4.8 Hz, 1H),7.34 (dd, J=2.6, 1.4 Hz, 1H), 7.16-7.01 (m, 4H). LCMS: rt4.96 min (A),purity 99%, MS (m/e) 314 (MH⁺).

5-(2-(3-(Methyl-d3)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 602). LCMS: rt5.00 min (A), purity 99%, MS (m/e) 290 (MH⁺).

6-(2-(3-(Methyl-d₃)phenyl)pyridin-3-yl)benzo[d]thiazole (Compound 603).LCMS: rt5.15 min (A), purity 99%, MS (m/e) 306 (MH⁺).

7-(2-(3-(Methyl-d₃)phenyl)pyridin-3-yl)imidazo[1,5-a]pyridine (Compound604). LCMS: rt3.35 min (A), purity 99%, MS (m/e) 289 (MH⁺).

6-(2-(3-(Methyl-d₃)phenyl)pyridin-3-yl)quinoxaline (Compound 605). ¹HNMR (300 MHz, DMSO-d₆): δ 8.87 (s, 2H), 8.67 (dd, J=4.7, 1.6 Hz, 1H),8.00-7.93 (m, 2H), 7.89 (d, J=8.7 Hz, 1H), 7.53-7.43 (m, 2H), 7.24 (s,1H), 6.99 (dt, J=7.5, 4.1 Hz, 2H), 6.90 (ddd, J=5.0, 2.7, 1.5 Hz, 1H).LCMS: rt4.83 min (A), purity 99%, MS (m/e) 301 (MH⁺).

1-(6-(2-(3-(Methyl-d₃)phenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one(Compound 606). LCMS: rt 4.25 min (A), purity 99%, MS (m/e) 331 (MH⁺).

N-(2-(Dimethylamino)ethyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 607). LCMS: rt2.62 min (B), purity 99%, MS (m/e) 418 (MH⁺).

N-(3-(Dimethylamino)propyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 608). LCMS: rt2.62 min (B), purity 99%, MS (m/e) 432 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-morpholinopropyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 609). LCMS: rt2.64 min (B), purity 99%, MS (m/e) 474 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(pyrrolidin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 610). LCMS: rt2.72 min (B), purity 99%, MS (m/e) 444 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(piperidin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 611). LCMS: rt2.78 min (B), purity 99%, MS (m/e) 472 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 612). ¹H NMR (300 MHz, DMSO-d₆): δ 9.47 (s, 1H), 8.71 (dd,J=4.7, 1.5 Hz, 1H), 8.51 (t, J=4.9 Hz, 1H), 8.31 (s, 1H), 7.95 (d, J=7.8Hz, 1H), 7.57 (app d, J=9.5 Hz, 1H), 7.52 (dd, J=7.7, 4.8 Hz, 1H), 7.43(d, J=7.9 Hz, 1H), 7.05 (d, J=9.2 Hz, 2H), 6.97 (app dd, J=17.6, 9.1 Hz,1H), 3.34 (t, J=6.8 Hz, 2H), 3.23 (t, J=6.8 Hz, 4H), 2.21 (t, J=8.1 Hz,2H), 2.16 (s, 3H), 1.99-1.82 (m, 2H), 1.80-1.64 (m, 2H). ¹⁹F NMR (282MHz, DMSO-d₆): δ −118.24 (s). LCMS: rt2.94 min (B), purity 99%, MS (m/e)472 (MH⁺).

N-(2,3-Dihydroxypropyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 613). LCMS: rt 4.15 min (A), purity 99%, MS (m/e) 421 (MH⁺).

(S)-2-((tert-Butoxycarbonyl)amino)-3-(1H-indol-3-yl)propyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylate(Compound 614). ¹H NMR (300 MHz, DMSO-d₆): δ 10.81 (s, 1H), 9.13 (s,1H), 8.71 (dd, J=4.7, 1.6 Hz, 1H), 8.33 (s, 1H), 7.97 (dd, J=7.7, 1.5Hz, 1H), 7.66 (d, J=9.3 Hz, 1H), 7.57-7.46 (m, 2H), 7.42 (dd, J=8.1, 1.6Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.13 (app dd, J=4.1, 1.9 Hz, 2H), 7.04(app t, J=7.7 Hz, 3H), 6.99-6.90 (m, 2H), 4.29 (dd, J=10.3, 4.9 Hz, 1H),4.19 (app qt, J=6.9 Hz, 1H), 2.90 (t, J=8.7 Hz, 2H), 2.14 (s, 3H), 1.28(s, 9H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.18 (s). LCMS: rt7.10 min(A), purity 99%, MS (m/e) 620 (MH⁺).

(S)-2-Amino-3-(1H-indol-3-yl)propyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylateformic acid salt (Compound 615). LCMS: rt5.10 min (A), purity 99%, MS(m/e) 520 (MH⁺—HCOOH).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-sulfamoylphenyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 616). LCMS: rt 4.05 min (A), purity 99%, MS (m/e) 502 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(4-sulfamoylphenyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 617). LCMS: rt 4.71 min (A), purity 99%, MS (m/e) 502 (MH⁺).

N-(4-Carbamoylphenyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 618). LCMS: rt 4.48 min (A), purity 99%, MS (m/e) 466 (MH⁺).

N-(3-Carbamoylphenyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 619). ¹H NMR (300 MHz, DMSO-d₆): δ 10.59 (s, 1H), 9.73-9.51(m, 1H), 8.82 (s, 1H), 8.80-8.72 (m, 1H), 8.24 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.95-7.89 (m, 1H), 7.76 (d, J=9.3 Hz, 1H), 7.63 (dd, J=7.9, 4.7Hz, 2H), 7.45 (dd, J=16.4, 8.5 Hz, 2H), 7.33-7.24 (m, 1H), 7.12 (dd,J=8.0, 5.4 Hz, 1H), 6.99 (app t, J=9.3 Hz, 1H), 6.95 (br s, 2H), 2.18(s, 3H). LCMS: rt 4.56 min (A), purity 96%, MS (m/e) 466 (MH⁺).

(R)-2-Amino-3-(1H-indol-3-yl)propyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylateformicacid salt (Compound 620). ¹H NMR (300 MHz, DMSO-d₆): δ 10.85 (s, 1H),9.16 (s, 1H), 8.71 (dd, J=4.7, 1.7 Hz, 1H), 7.96 (dd, J=7.6, 1.7 Hz,1H), 7.67 (d, J=8.9 Hz, 1H), 7.57-7.45 (m, 2H), 7.42 (d, J=8.1 Hz, 1H),7.32 (d, J=8.0 Hz, 1H), 7.22-7.10 (m, 2H), 7.12-6.98 (m, 2H), 7.00-6.86(m, 2H), 4.40-3.91 (m, 2H), 3.38-3.33 (m, 1H), 3.02-2.68 (m, 2H), 2.15(s, 3H). LCMS: rt 5.10 min (A), purity 98%, MS (m/e) 520 (MH⁺—HCOOH).

6-(2-(3-Fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 621). LCMS: rt5.64 min (A), purity 99%, MS (m/e) 315 (MH⁺).

6-(2-(3,4-Difluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 622). LCMS: rt6.19 min (A), purity 99%, MS (m/e) 333 (MH⁺).

6-(2-(2-Fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 623). LCMS: rt5.55 min (A), purity 99%, MS (m/e) 333 (MH⁺).

6-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 624). LCMS: rt6.02 min (A), purity 99%, MS (m/e) 333 (MH⁺).

6-(2-(4-Fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 625). LCMS: rt5.24 min (A), purity 99%, MS (m/e) 333 (MH⁺).

6-(2-(3-Methoxyphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 626). LCMS: rt4.97 min (A), purity 99%, MS (m/e) 333 (MH⁺).

6-(2-(3-Cyanophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 627). LCMS: rt5.77 min (A), purity 99%, MS (m/e) 333 (MH⁺).

6-(2-(3-Cyano-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 628). LCMS: rt6.29 min (A), purity 99%, MS (m/e) 333 (MH⁺).

(R)-2-Amino-3-(1H-indol-3-yl)propyl5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxylateTFA salt (Compound 628). LCMS: rt5.15 min (A), purity 95%, MS (m/e) 520(MH⁺-TFA).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)-1H-indazole-1-carboxamide(Compound 630). LCMS: rt6.71 min (A), purity 98%, MS (m/e) 513 (MH⁺).

N-(3,4-Dimethoxybenzyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamide(Compound 631). ¹H NMR (300 MHz, DMSO-d₆): δ 8.92 (t, J=6.3 Hz, 1H),8.66 (dd, J=4.7, 1.7 Hz, 1H), 8.37 (d, J=0.7 Hz, 1H), 8.13 (d, J=8.7 Hz,1H), 7.86 (dd, J=7.7, 1.7 Hz, 1H), 7.73 (s, 1H), 7.47 (dd, J=7.8, 4.7Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.28 (dd, J=8.7, 1.7 Hz, 1H), 7.01 (s,1H), 6.95-6.84 (m, 4H), 4.39 (d, J=6.3 Hz, 2H), 3.72 (s, 3H), 3.70 (s,3H), 2.12 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.67 (d, J=7.8 Hz).LCMS: rt 7.05 min (A), purity 99%, MS (m/e) 497 (MH⁺).

N-(2-(1H-Indol-3-yl)ethyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamide(Compound 632). LCMS: rt 6.48 min (A), purity 99%, MS (m/e) 490 (MH⁺).

N-(2-(Dimethylamino)ethyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamide(Compound 633). LCMS: rt 4.16 min (A), purity 98%, MS (m/e) 418 (MH⁺).

N-(3-(Dimethylamino)propyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamide(Compound 634). LCMS: rt 5.30 min (A), purity 98%, MS (m/e) 431 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)-1H-indazole-1-carboxamide(Compound 635). LCMS: rt 5.30 min (A), purity 97%, MS (m/e) 472 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-indazole-1-carboxamide(Compound 636). LCMS: rt 4.33 min (A), purity 99%, MS (m/e) 444 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(piperidin-1-yl)propyl)-1H-indazole-1-carboxamide(Compound 637). LCMS: rt 4.53 min (A), purity 98%, MS (m/e) 472 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-morpholinopropyl)-1H-indazole-1-carboxamide(Compound 638). LCMS: rt4.21 min (A), purity 99%, MS (m/e) 474 (MH⁺).

N-(2-Aminoethyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamide(Compound 639). LCMS: rt 4.00 min (A), purity 99%, MS (m/e) 390 (MH⁺).

N-(3-Aminopropyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamide(Compound 640). LCMS: rt 3.41 min (A), purity 99%, MS (m/e) 404 (MH⁺).

(S)-2-((tert-Butoxycarbonyl)amino)-3-(1H-indol-3-yl)propyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(Compound 641). ¹H NMR (300 MHz, DMSO-d₆): δ 10.82 (s, 1H), 9.17 (s,1H), 8.71 (d, J=4.7 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.70 (d, J=9.8 Hz,2H), 7.60-7.38 (m, 3H), 7.32 (d, J=8.1 Hz, 1H), 7.21-6.86 (m, 6H), 6.75(d, J=9.3 Hz, 1H), 4.45-4.29 (m, 1H), 4.23 (t, J=9.6 Hz, 1H), 4.13-4.02(m, 1H), 2.92 (d, J=6.4 Hz, 2H), 2.15 (s, 3H), 1.27 (s, 9H). LCMS: rt7.41 min (A), purity 96%, MS (m/e) 620 (MH⁺).

(R)-2-((tert-Butoxycarbonyl)amino)-3-(1H-indol-3-yl)propyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(Compound 642). LCMS: rt7.41 min (A), purity 96%, MS (m/e) 620 (MH⁺).

(S)-2-((tert-Butoxycarbonyl)amino)-3-(1H-indol-3-yl)propyl7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(Compound 643). ¹H NMR (300 MHz, DMSO-d₆): δ 10.82 (s, 1H), 8.96 (d,J=7.4 Hz, 1H), 8.80-8.63 (m, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.86 (s, 1H),7.71 (s, 1H), 7.66-7.40 (m, 3H), 7.31 (d, J=7.8 Hz, 1H), 7.15 (s, 1H),7.00 (ddd, J=12.4, 7.2, 3.1 Hz, 5H), 6.67 (d, J=7.4 Hz, 1H), 4.36 (dd,J=10.7, 4.3 Hz, 1H), 4.28-4.13 (m, 1H), 4.13-4.01 (m, 1H), 2.91 (d,J=6.3 Hz, 2H), 2.17 (s, 3H), 1.28 (s, 9H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−118.08 (s). LCMS: rt 7.36 min (A), purity 99%, MS (m/e) 620 (MH⁺).

(R)-2-((tert-Butoxycarbonyl)amino)-3-(1H-indol-3-yl)propyl7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate(Compound 644). LCMS: rt 7.36 min (A), purity 99%, MS (m/e) 620 (MH⁺).

(S)-2-Amino-3-(1H-indol-3-yl)propyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylateformic acid salt (Compound 645). LCMS: rt 5.45 min (A), purity 99%, MS(m/e) 520 (MH⁺—HCOOH).

(R)-2-Amino-3-(1H-indol-3-yl)propyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylateformic acid salt (Compound 646). LCMS: rt 5.45 min (A), purity 99%, MS(m/e) 520 (MH⁺—HCOOH).

(S)-2-Amino-3-(1H-indol-3-yl)propyl7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylateformic acid salt (Compound 647). LCMS: rt 5.41 min (A), purity 99%, MS(m/e) 520 (MH⁺—HCOOH).

(R)-2-Amino-3-(1H-indol-3-yl)propyl7-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylateformicacid salt (Compound 648). LCMS: rt 5.41 min (A), purity 99%, MS (m/e)520 (MH⁺—HCOOH).

N-((1R,2R)-2-Aminocyclohexyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamidehydrochloride salt (Compound 649). ¹H NMR (300 MHz, DMSO-d₆): δ 8.82 (d,J=5.2 Hz, 1H), 8.71 (s, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.42 (d, J=0.7 Hz,1H), 8.32 (d, J=7.8 Hz, 1H), 8.16 (d, J=8.8 Hz, 3H), 7.95-7.81 (m, 1H),7.80 (s, 1H), 7.48 (d, J=6.7 Hz, 1H), 7.33 (dd, J=8.7, 1.6 Hz, 1H),7.16-6.89 (m, 2H), 3.75-3.52 (m, 2H), 3.46 (dd, J=8.0, 4.0 Hz, 1H), 2.12(s, 3H), 1.94-1.78 (m, 1H), 1.75-1.55 (m, 3H), 1.50-1.35 (m, 1H),1.31-1.02 (m, 2H). LCMS: rt 4.63 min (A), purity 92%, MS (m/e) 444(MH⁺—HCl).

N-((1S,2S)-2-Aminocyclohexyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamide(Compound 650). LCMS: rt 4.58 min (A), purity 94%, MS (m/e) 444(MH⁺—HCl).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-((1-methylpiperidin-4-yl)methyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 651). LCMS: rt 3.70 min (A), purity 99%, MS (m/e) 458 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 652). LCMS: rt 3.56 min (A), purity 98%, MS (m/e) 430 (MH⁺).

N-(3-(1H-Imidazol-1-yl)propyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 653). LCMS: rt 3.71 min (A), purity 99%, MS (m/e) 455 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(pyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 654). ¹H NMR (300 MHz, DMSO-d₆): δ 10.50 (s, 1H), 9.44 (s,1H), 8.73 (d, J=4.7 Hz, 1H), 8.63 (s, 1H), 8.46 (d, J=6.2 Hz, 2H), 7.98(d, J=7.7 Hz, 1H), 7.73 (d, J=6.3 Hz, 2H), 7.65 (d, J=9.3 Hz, 1H), 7.53(dd, J=7.8, 4.7 Hz, 1H), 7.45 (d, J=6.9 Hz, 1H), 7.20-7.04 (m, 2H),7.03-6.90 (m, 1H), 2.17 (s, 3H). LCMS: rt 4.08 min (A), purity 99%, MS(m/e) 424 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 655). ¹H NMR (300 MHz, DMSO-d₆): δ 8.71-8.62 (m, 1H), 8.57 (d,J=7.2 Hz, 1H), 8.53 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 8.05 (d, J=7.2 Hz,1H), 7.92-7.83 (m, 1H), 7.47 (dd, J=7.8, 4.8 Hz, 1H), 7.39 (d, J=6.0 Hz,1H), 6.99 (dd, J=5.3, 2.3 Hz, 1H), 6.93 (t, J=9.0 Hz, 1H), 6.57 (dd,J=7.1, 2.0 Hz, 1H), 3.96-3.82 (m, 1H), 3.22-3.11 (m, 2H), 2.80-2.63 (m,2H), 2.56 (s, 3H), 2.12 (s, 3H), 1.95-1.82 (m, 2H), 1.68-1.65 (m, 2H).LCMS: rt 4.03 min (A), purity 99%, MS (m/e) 444 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-((1-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 656). LCMS: rt 4.06 min (A), purity 99%, MS (m/e) 458 (MH⁺).

6-(2-(2-Fluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound 657). LCMS:rt 5.60 min (A), purity 99%, MS (m/e) 307 (MH⁺).

6-(2-(3-Fluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound 658). LCMS:rt 5.65 min (A), purity 99%, MS (m/e) 307 (MH⁺).

6-(2-(4-Fluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound 659). LCMS:rt 5.25 min (A), purity 99%, MS (m/e) 307 (MH⁺).

6-(2-(3,5-Difluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound 660).LCMS: rt 6.32 min (A), purity 99%, MS (m/e) 325 (MH⁺).

6-(2-(3,4-Difluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound 661).LCMS: rt 6.25 min (A), purity 99%, MS (m/e) 325 (MH⁺).

6-(2-(2,3-Difluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound 662).LCMS: rt 6.58 min (A), purity 99%, MS (m/e) 325 (MH⁺).

N-((1R,2R)-2-Aminocyclohexyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 663). LCMS: rt 4.40 min (A), purity 99%, MS (m/e) 444 (MH⁺).

N-((1S,2S)-2-Aminocyclohexyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 664). LCMS: rt 4.38 min (A), purity 99%, MS (m/e) 444 (MH⁺).

6-(2-(2,4-Difluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound 665).LCMS: rt 6.60 min (A), purity 99%, MS (m/e) 325 (MH⁺).

6-(2-(3,4,5-Trifluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound666). LCMS: rt 5.54 min (B), purity 99%, MS (m/e) 343 (MH⁺).

6-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)benzo[d]thiazole (Compound667). LCMS: rt 5.91 min (A), purity 99%, MS (m/e) 321 (MH⁺).

6-(2-(3-Chlorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound 668). ¹HNMR (300 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.72 (dd, J=4.8, 1.7 Hz, 1H),8.12 (d, J=1.8 Hz, 1H), 8.04-7.88 (m, 2H), 7.55 (dd, J=7.8, 4.8 Hz, 1H),7.43 (t, J=1.9 Hz, 1H), 7.34-7.28 (m, 1H), 7.26 (dd, J=8.4, 1.8 Hz, 1H),7.20 (t, J=7.8 Hz, 1H), 7.11 (dt, J7.7, 1.4 Hz, 1H). LCMS: rt 6.20 min(A), purity 99%, MS (m/e) 323 (MH⁺).

6-(2-(3-Methoxyphenyl)pyridin-3-yl)benzo[d]thiazole (Compound 669).LCMS: rt 5.05 min (A), purity 99%, MS (m/e) 319 (MH⁺).

3-(3-(Benzo[d]thiazol-6-yl)pyridin-2-yl)benzonitrile (Compound 670).LCMS: rt5.93 min (A), purity 99%, MS (m/e) 314 (MH⁺).

6-(2-(Benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)benzo[d]thiazole (Compound671). LCMS: rt 4.78 min (A), purity 99%, MS (m/e) 333 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-morpholinopropyl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 672). LCMS: rt min 2.86 (B), purity 99%, MS (m/e) 474 (MH⁺).

N-(2-(Dimethylamino)ethyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 673). LCMS: rt 2.72 min (B), purity 99%, MS (m/e) 418 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (Compound 674). LCMS: rt2.80 min (B), purity 99%, MS (m/e) 460 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 675). LCMS: rt2.91 min (B), purity 99%, MS (m/e) 458 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 676). LCMS: rt 2.47 min (B), purity 99%, MS (m/e) 487 (MH⁺).

Ethyl5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylate(Compound 677). ¹H NMR (300 MHz, DMSO-d₆): δ 8.76 (dd, J=7.2, 0.9 Hz,1H), 8.72 (dd, J=4.8, 1.7 Hz, 1H), 8.44 (s, 1H), 7.99 (dd, J=7.8, 1.7Hz, 1H), 7.94 (dd, J=2.1, 0.9 Hz, 1H), 7.53 (dd, J=7.8, 4.8 Hz, 1H),7.45 (dd, J=7.7, 1.8 Hz, 1H), 7.10-6.94 (m, 2H), 6.80 (dd, J=7.2, 2.0Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 2.17 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.06-−118.13 (m). LCMS: rt 6.51 min(A), purity 96%, MS (m/e) 376 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylicacid (Compound 678). ¹H NMR (300 MHz, DMSO-d₆): δ 12.47 (s, 1H),8.76-8.65 (m, 2H), 8.39 (s, 1H), 8.05-7.91 (m, 2H), 7.52 (dd, J=7.8, 4.8Hz, 1H), 7.45 (dd, J=7.5, 2.2 Hz, 1H), 7.11-6.90 (m, 2H), 6.71 (dd,J=7.2, 2.0 Hz, 1H), 2.17 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.05.LCMS: rt 5.01 min (A), purity 97%, MS (m/e) 348 (MH⁺).

N-((1R,2R)-2-Aminocyclohexyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 679). ¹H NMR (300 MHz, DMSO-d₆): δ 9.48 (s, 1H), 8.70 (d,J=4.4 Hz, 1H), 8.37 (s, 1H), 8.27-8.13 (m, 1H), 7.93 (dd, J=7.8, 1.4 Hz,1H), 7.62-7.46 (m, 2H), 7.43 (dd, J=7.8, 2.0 Hz, 1H), 7.12-6.84 (m, 3H),3.75-3.52 (m, 2H), 3.46 (dd, J=8.0, 4.0 Hz, 1H), 2.12 (s, 3H), 1.94-1.78(m, 1H), 1.75-1.55 (m, 3H), 1.50-1.35 (m, 1H), 1.31-1.02 (m, 2H). LCMS:rt 4.05 min (A), purity 98%, MS (m/e) 444 (MH⁺).

N-((1S,2S)-2-Aminocyclohexyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 680). LCMS: rt 4.00 min (A), purity 98%, MS (m/e) 444 (MH⁺).

N-(2-Aminoethyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 681). ¹H NMR (300 MHz, DMSO-d₆): δ 9.48 (s, 1H), 9.04 (t,J=5.6 Hz, 1H), 8.78 (dd, J=4.9, 0.7 Hz, 1H), 8.56 (s, 1H), 8.27-8.13 (m,3H), 7.93 (dd, J=7.8, 1.4 Hz, 1H), 7.62 (dd, J=7.8, 4.9 Hz, 1H), 7.44(d, J=7.5 Hz, 1H), 7.35 (dd, J=9.3, 1.1 Hz, 1H), 7.15-7.04 (m, 1H), 6.98(t, J=9.1 Hz, 1H), 3.54 (q, J=5.9 Hz, 2H), 3.02 (dd, J=11.6, 5.8 Hz,2H), 2.16 (s, 3H). LCMS: rt 3.48 min (A), purity 98%, MS (m/e) 390(MH⁺).

N-(3-Aminopropyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 682). LCMS: rt 3.53 min (A), purity 98%, MS (m/e) 404 (MH⁺).

N-(2-Aminoethyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 683). LCMS: rt 3.88 min (A), purity 98%, MS (m/e) 390 (MH⁺).

N-(3-Aminopropyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 684). LCMS: rt 3.93 min (A), purity 98%, MS (m/e) 404 (MH⁺).

Methyl6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylate(Compound 685). ¹H NMR (300 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.72 (dd,J=4.7, 1.4 Hz, 1H), 8.31 (s, 1H), 7.97 (dd, J=7.7, 1.5 Hz, 1H), 7.68 (d,J=9.2 Hz, 1H), 7.53 (dd, J=7.8, 4.7 Hz, 1H), 7.43 (dd, J=7.6, 1.9 Hz,1H), 7.18 (dd, J=9.2, 1.6 Hz, 1H), 7.12-7.01 (m, 1H), 6.97 (t, J=9.1 Hz,1H), 3.87 (s, 3H), 2.16 (s, 3H). LCMS: rt 5.08 min (A), purity 96%, MS(m/e) 362 (MH⁺).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound686). ¹H NMR (300 MHz, DMSO-d₆): δ 9.40 (d, J=0.7 Hz, 1H), 8.70 (dd,J=4.7, 1.6 Hz, 1H), 8.13 (dd, J=1.8, 0.6 Hz, 1H), 7.99 (dd, J=8.4, 0.7Hz, 1H), 7.93 (dd, J=7.7, 1.7 Hz, 1H), 7.60-7.47 (m, 2H), 7.27 (dd,J=8.5, 1.8 Hz, 1H), 7.22 (d, J=9.3 Hz, 1H), 7.13 (ddd, J=8.6, 4.9, 2.2Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.36 (td, J=8.5, 8.0, 5.0 Hz).LCMS: rt 6.37 min (A), purity 99%, MS (m/e) 341 (MH⁺).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 687). LCMS: rt 4.53 min (A), purity 99%, MS (m/e) 324 (MH⁺).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinoline (Compound 688).LCMS: rt 5.03 min (A), purity 99%, MS (m/e) 335 (MH⁺).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 689). ¹H NMR (300 MHz, DMSO-d₆): δ 8.74 (ddd, J=4.8, 1.7, 0.8Hz, 1H), 8.69 (dt, J=1.8, 0.9 Hz, 1H), 8.47 (d, J=0.8 Hz, 1H), 8.09(ddd, J=7.7, 1.7, 0.8 Hz, 1H), 7.76-7.64 (m, 2H), 7.57 (ddd, J=7.8, 4.8,0.8 Hz, 1H), 7.34-7.25 (m, 2H), 7.13 (ddd, J=9.3, 1.8, 0.8 Hz, 1H). ¹⁹FNMR (282 MHz, DMSO-d₆): δ −116.87 (q, J=7.8 Hz). LCMS: rt 6.58 min (A),purity 99%, MS (m/e) 349 (MH⁺).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinoxaline (Compound 690).LCMS: rt 6.48 min (A), purity 99%, MS (m/e) 336 (MH⁺).

2-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-1,5-naphthyridine (Compound691). LCMS: rt 6.23 min (A), purity 99%, MS (m/e) 336 (MH⁺).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 692). ¹H NMR (300 MHz, DMSO-d₆): δ 9.05 (dd, J=1.8, 0.9 Hz,1H), 8.74 (dd, J=4.8, 1.7 Hz, 1H), 8.52 (s, 1H), 8.03 (dd, J=7.8, 1.7Hz, 1H), 7.73 (dd, J=9.2, 0.9 Hz, 1H), 7.67 (ddd, J=7.3, 1.9, 0.6 Hz,1H), 7.56 (dd, J=7.8, 4.8 Hz, 1H), 7.32-7.23 (m, 3H). LCMS: rt 5.80 min(A), purity 99%, MS (m/e) 325 (MH⁺).

6-(2-(2,4,5-Trifluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound693). ¹H NMR (300 MHz, DMSO-d₆): δ 9.00 (dd, J=4.3, 1.8 Hz, 1H),8.85-8.76 (m, 1H), 8.39 (d, J=8.7 Hz, 1H), 8.31 (d, J=8.9 Hz, 1H), 8.18(ddd, J=7.8, 1.7, 0.6 Hz, 1H), 7.80 (dd, J=8.5, 4.2 Hz, 1H), 7.66-7.56(m, 2H), 7.53 (d, J=8.7 Hz, 1H), 7.24 (t, J=9.0 Hz, 1H), 7.10 (ddd,J=8.7, 4.9, 2.3 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −116.93 (td,J=8.1, 5.5 Hz). LCMS: rt 7.16 min (A), purity 99%, MS (m/e) 343 (MH⁺).

6-(2-(2,4,5-Trifluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 694). LCMS: rt 4.41 min (A), purity 99%, MS (m/e) 326 (MH⁺).

6-(2-(2,4,5-Trifluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 695). LCMS: rt 6.61 min (A), purity 99%, MS (m/e) 351 (MH⁺).

6-(2-(2,4,5-Trifluorophenyl)pyridin-3-yl)quinoline (Compound 696). LCMS:rt 5.06 min (A), purity 99%, MS (m/e) 337 (MH⁺).

6-(2-(3-Chlorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 697). ¹H NMR (300 MHz, DMSO-d₆): δ 8.75 (dd, J=4.8, 1.7 Hz,1H), 8.68 (dd, J=1.8, 1.0 Hz, 1H), 8.46 (s, 1H), 8.09 (dd, J=7.8, 1.7Hz, 1H 7.67 (dd, J=9.3, 1.0 Hz, 1H), 7.58-7.55 (app m, 2H), 7.44-7.30(m, 1H), 7.25 (appd, J=4.8 Hz, 1H), 7.12 (dd, J=9.3, 1.8 Hz, 1H). LCMS:rt 6.15 min (A), purity 99%, MS (m/e) 331 (MH⁺).

6-(2-(3-Chlorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound 698).LCMS: rt 4.16 min (A), purity 99%, MS (m/e) 306 (MH⁺).

6-(2-(3-Chlorophenyl)pyridin-3-yl)quinolone (Compound 699). LCMS: rt4.65 min (A), purity 99%, MS (m/e) 317 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(1-isopropylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 700). ¹H NMR (300 MHz, DMSO-d₆): δ 9.46 (s, 1H), 8.70 (d,J=4.2 Hz, 1H), 8.35 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.8 Hz,1H), 7.62-7.36 (m, 3H), 7.14-6.84 (m, 3H), 3.77-3.70 (m, 1H), 2.82 (d,J=10.0 Hz, 2H), 2.72 (dt, J=14.0, 7.0 Hz, 1H), 2.15 (s, 4H), 1.81 (d,J=11.4 Hz, 2H), 1.66-1.35 (m, 2H), 0.97 (d, J=6.5 Hz, 6H). LCMS: rt 3.21min (B), purity 99%, MS (m/e) 472 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(1-isopropylpiperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 701). LCMS: rt 3.53 min (B), purity 99%, MS (m/e) 472 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 702). LCMS: rt 2.90 min (A), purity 99%, MS (m/e) 500 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 703). ¹H NMR (300 MHz, DMSO-d₆): δ 8.71 (dd, J=4.9, 1.7 Hz,1H), 8.59 (d, J=7.3 Hz, 1H), 8.56 (s, 1H), 8.21 (s, 1H), 7.93 (t, J=8.2Hz, 2H), 7.51 (dd, J=7.8, 4.7 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.14-6.89(m, 2H), 6.57 (dd, J=7.3, 2.1 Hz, 1H), 4.37-3.93 (m, 1H), 2.18 (s, 6H),1.71 (dd, J=12.7, 3.4 Hz, 2H), 1.39 (t, J=12.3 Hz, 2H), 1.08 (s, 6H),1.02 (s, 6H). LCMS: rt 3.16 min (A), purity 99%, MS (m/e) 500 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-hydroxypropyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 704). ¹H NMR (300 MHz, DMSO-d₆): δ 9.48 (dd, J=1.9, 1.0 Hz,1H), 8.70 (dd, J=4.7, 1.6 Hz, 1H), 8.47 (t, J=5.7 Hz, 1H), 8.31 (s, 1H),7.93 (dd, J=7.8, 1.6 Hz, 1H), 7.60-7.46 (m, 2H), 7.43 (dd, J=7.9, 1.8Hz, 1H), 7.13-6.87 (m, 3H), 4.54-4.33 (app m, 1H), 3.46 (q, J=5.8 Hz,2H), 3.39-3.29 (m, 2H), 2.16 (s, 3H), 1.81-1.55 (m, 2H). ¹⁹F NMR (282MHz, DMSO-d₆): δ −118.29. LCMS: rt 3.95 min (A), purity 99%, MS (m/e)405 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-hydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 705). LCMS: rt 3.85 min (A), purity 99%, MS (m/e) 391 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-hydroxypropyl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 706). ¹H NMR (300 MHz, DMSO-d₆): δ 8.71 (ddd, J=4.8, 1.7, 0.6Hz, 1H), 8.60 (d, J=7.2 Hz, 1H), 8.52 (s, 1H), 8.25-8.07 (m, 2H), 7.94(dd, J=7.8, 1.7 Hz, 1H), 7.51 (dd, J=7.8, 4.8 Hz, 1H), 7.45 (dd, J=7.5,1.9 Hz, 1H), 7.06 (ddd, J=7.6, 5.2, 2.3 Hz, 1H), 7.02-6.92 (app m, 1H),6.57 (dd, J=7.2, 2.0 Hz, 1H), 4.46 (t, J=5.2 Hz, 1H), 3.45 (q, J=6.1 Hz,2H), 3.28-3.25 (q, J=6.1 Hz, 2H), 2.17 (s, 3H), 1.67 (q, J=6.7 Hz, 2H).¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.29 (s). LCMS: rt 4.50 min (A), purity99%, MS (m/e) 405 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 707). LCMS: rt 4.35 min (A), purity 99%, MS (m/e) 391 (MH⁺).

6-(2-(3-Chlorophenyl)pyridin-3-yl)-N-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 708). ¹H NMR (300 MHz, DMSO-d₆): δ 9.48 (dd, J=1.9, 0.9 Hz,1H), 8.74 (dd, J=4.8, 1.6 Hz, 1H), 8.36 (s, 1H), 8.27 (d, J=7.8 Hz, 1H),7.97 (dd, J=7.8, 1.7 Hz, 1H), 7.62-7.52 (m, 2H), 7.49 (ddd, J=2.2, 1.5,0.7 Hz, 1H), 7.35 (dt, J=7.5, 2.0 Hz, 1H), 7.31-7.14 (m, 2H), 7.05 (ddd,J=9.3, 1.9, 0.6 Hz, 1H), 3.84-3.61 (m, 1H), 2.76 (d, J=12.8 Hz, 2H),2.15 (s, 3H), 2.04-1.86 (m, 2H), 1.77 (d, J=11.1 Hz, 2H), 1.67-1.45 (m,2H). LCMS: rt 3.96 min (A), purity 99%, MS (m/e) 446 (MH⁺).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 709). LCMS: rt 4.21 min (A), purity 99%, MS (m/e) 464 MH⁺).

N-(1-Methylpiperidin-4-yl)-6-(2-(2,4,5-Trifluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 710). LCMS: rt 4.10 min (A), purity 99%, MS (m/e) 466 (MH⁺).

rac-6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 711). LCMS: rt 2.66 min (B), purity 99%, MS (m/e) 470 (MH⁺).

exo-6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 712). LCMS: rt 2.73 min (B), purity 99%, MS (m/e) 470 (MH⁺).

endo-6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 713). LCMS: rt 2.67 min (B), purity 99%, MS (m/e) 470 (MH⁺).

rac-5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 714). LCMS: rt 3.42 min (B), purity 99%, MS (m/e) 470 (MH⁺).

exo-5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 715). LCMS: rt 3.44 min (B), purity 99%, MS (m/e) 470 (MH⁺).

endo-5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 716). LCMS: rt 3.46 min (B), purity 99%, MS (m/e) 470 (MH⁺).

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound717). ¹H NMR (300 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.72 (dd, J=4.8, 1.7Hz, 1H), 8.09 (dd, J=1.8, 0.6 Hz, 1H), 8.02-7.89 (m, 2H), 7.66-7.54 (m,2H), 7.40 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.27 (dd, J=8.5, 1.8 Hz, 1H),7.03 (appt, J=8.8 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.29 (s).LCMS: rt 7.31 min (A), purity 99%, MS (m/e) 341 (MH⁺).

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)benzo[d]thiazole(Compound 718). ¹H NMR (300 MHz, DMSO-d₆): δ 9.38 (d, J=0.6 Hz, 1H),8.73 (ddd, J=4.8, 1.7, 0.6 Hz, 1H), 8.11 (dd, J=1.8, 0.6 Hz, 1H),8.03-7.95 (m, 2H), 7.80 (dd, J=8.4, 7.4 Hz, 1H), 7.61 (dd, J=7.8, 4.8Hz, 1H), 7.33 (app t, J=9.2 Hz, 1H, 7.28 (dd, J=9.1 Hz, 1H), 7.38-7.24(m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −111.43 (q, J=8.7 Hz), −111.62(t, J=8.9 Hz). LCMS: rt7.66 min (A), purity 99%, MS (m/e) 359 (MH⁺).

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 719). LCMS: rt 6.76 min (A), purity 99%, MS (m/e) 349 (MH⁺).

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 720). LCMS: rt 7.08 min (A), purity 99%, MS (m/e) 367 (MH⁺).

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 721). LCMS: rt 4.61 min (A), purity 99%, MS (m/e) 324 (MH⁺).

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-N-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 722). LCMS: rt 4.23 min (A), purity 99%, MS (m/e) 464 (MH⁺).

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-N-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 723). ¹H NMR (300 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.75 (dd,J=4.6, 1.4 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.04 (dd,J=7.8, 1.5 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.72-7.54 (m, 2H), 7.38 (t,J=9.7 Hz, 1H), 7.20 (dd, J=9.3, 1.6 Hz, 1H), 3.92-3.60 (m, 1H), 2.82 (d,J=13.8 Hz, 2H), 2.21 (s, 3H), 2.03 (t, J=10.9 Hz, 2H), 1.79 (d, J=13.1Hz, 2H), 1.69-1.40 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −111.36 (q,J=9.1 Hz), −112.11 (q, J=8.7 Hz). LCMS: rt 4.43 min (A), purity 99%, MS(m/e) 482 (MH⁺).

N-(3-(2-Oxopyrrolidin-1-yl)propyl)-6-(2-(m-tolyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 724). LCMS: rt 4.08 min (A), purity 99%, MS (m/e) 454 (MH⁺).

6-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 725). LCMS: rt 4.58 min (A), purity 99%, MS (m/e) 472 (MH⁺).

6-(2-(3-Chlorophenyl)pyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 726). LCMS: rt 4.73 min (A), purity 99%, MS (m/e) 474 (MH⁺).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 727). LCMS: rt 5.00 min (A), purity 99%, MS (m/e) 492 (MH⁺).

N-(3-(2-Oxopyrrolidin-1-yl)propyl)-6-(2-(2,4,5-Trifluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 728). LCMS: rt 4.95 min (A), purity 99%, MS (m/e) 494 (MH⁺).

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 729). ¹H NMR (300 MHz, DMSO-d₆): δ 9.48 (s, 1H), 8.78 (dd,J=4.8, 1.6 Hz, 1H), 8.63 (t, J=5.5 Hz, 1H), 8.43 (s, 1H), 8.05 (dd,J=7.8, 1.6 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H), 7.70-7.56 (m, 2H), 7.50-7.31(m, 2H), 7.08 (t, J=9.2 Hz, 1H), 3.34 (t, J=7.0 Hz, 2H), 3.22 (t, J=7.0Hz, 4H), 2.20 (t, J=8.0 Hz, 2H), 1.91 (p, J=7.5 Hz, 2H), 1.71 (p, J=7.2Hz, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.76 (ddd, J=10.0, 5.9, 4.2Hz). LCMS: rt5.03 min (A), purity 99%, MS (m/e) 492 (MH⁺).

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 730). LCMS: rt 5.25 min (A), purity 99%, MS (m/e) 510 (MH⁺).

7-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 731). LCMS: rt 4.85 min (A), purity 99%, MS (m/e) 305 (MH⁺).

7-(2-(m-Tolyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (Compound732). LCMS: rt 4.40 min (A), purity 99%, MS (m/e) 287 (MH⁺).

7-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 733). LCMS: rt 5.88 min (A), purity 99%, MS (m/e) 325 (MH⁺).

7-(2-(3-Chlorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 734). LCMS: rt 5.43 min (A), purity 99%, MS (m/e) 307 (MH⁺).

7-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 735). LCMS: rt 6.41 min (A), purity 99%, MS (m/e) 343 (MH⁺).

7-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 736). ¹H NMR (300 MHz, DMSO-d₆): δ 8.88 (dd, J=7.1, 0.9 Hz,1H), 8.78 (dd, J=4.8, 1.6 Hz, 1H), 8.49 (s, 1H), 8.07 (dd, J=7.9, 1.6Hz, 1H), 7.74 (dd, J=1.9, 0.9 Hz, 1H), 7.68 (dd, J=6.2, 2.8 Hz, 1H),7.64 (dd, J=7.9, 4.8 Hz, 1H), 7.46 (ddd, J=8.8, 4.4, 2.8 Hz, 1H), 7.09(dd, J=9.6, 8.9 Hz, 1H), 6.97 (dd, J=7.1, 1.9 Hz, 1H). LCMS: rt 6.10 min(A), purity 99%, MS (m/e) MH⁺325.

7-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 737). LCMS: rt min (A), purity 99%, MS (m/e) 305 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrido[2,3-b]pyrazine(Compound 738). LCMS: rt 5.06 min (A), purity 99%, MS (m/e) 317 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)pyrido[2,3-b]pyrazine (Compound 739).LCMS: rt 5.63 min (A), purity 99%, MS (m/e) 319 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[2,3-b]pyrazine(Compound 740). LCMS: rt 6.06 min (A), purity 99%, MS (m/e) 337 MH⁺.

6-(2-(2,4,5-Trifluorophenyl)pyridin-3-yl)pyrido[2,3-b]pyrazine (Compound741). LCMS: rt 6.03 min (A), purity 99%, MS (m/e) 339 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)pyrido[2,3-b]pyrazine(Compound 742). LCMS: rt 6.20 min (A), purity 99%, MS (m/e) 337 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)pyrido[2,3-b]pyrazine(Compound 743). LCMS: rt 6.56 min (A), purity 99%, MS (m/e) 355 MH⁺.

N-((7R,8aS)-5,5-Dimethyloctahydroindolizin-7-yl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 744). LCMS: rt 4.06 min (A), purity 99%, MS (m/e) 498 MH⁺.

N-((7R,8aS)-5,5-Dimethyloctahydroindolizin-7-yl)-5-(2-(4-difluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 745). ¹H NMR (300 MHz, DMSO-d₆): δ 8.71 (dd, J=4.8, 1.7 Hz,1H), 8.61-8.57 (m, 1H), 8.55 (s, 1H), 8.18 (dd, J=2.1, 0.9 Hz, 1H),8.02-7.79 (m, 2H), 7.52 (dd, J=7.8, 4.8 Hz, 1H), 7.45 (dd, J=8.0, 2.3Hz, 1H), 7.13-6.87 (m, 2H), 6.58 (dd, J=7.2, 2.1 Hz, 1H), 4.18-3.89 (m,1H), 2.84 (td, J=8.5, 3.3 Hz, 1H), 2.44-2.35 (m, 2H), 2.28 (q, J=8.5 Hz,1H), 2.17 (s, 3H), 1.95 (d, J=11.7 Hz, 1H), 1.87-1.71 (m, 1H), 1.69-1.54(m, 3H), 1.46-1.26 (m, 2H), 1.08 (s, 3H), 0.95 (s, 3H). ¹⁹F NMR (282MHz, DMSO-d₆): δ −118.10. LCMS: rt 4.45 min (A), purity 99%, MS (m/e)498 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 746). LCMS: rt 5.40 min (A), purity 99%, MS (m/e) 307 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 747). LCMS: rt 6.10 min (A), purity 99%, MS (m/e) 325 MH⁺.

6-(2-(2-Fluoro-5-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 748). LCMS: rt 5.21 min (A), purity 99%, MS (m/e) 305 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 749). ¹H NMR (300 MHz, DMSO-d₆): δ 9.01 (dd, J=1.8, 1.0 Hz,1H), 8.77 (dd, J=4.8, 1.6 Hz, 1H), 8.50 (s, 1H), 8.08 (dd, J=7.8, 1.6Hz, 1H), 7.86 (dd, J=8.5, 7.4 Hz, 1H), 7.76 (dd, J=9.2, 0.9 Hz, 1H),7.64 (dd, J=7.8, 4.8 Hz, 1H), 7.41 (dd, J=9.1 Hz, 0.9 Hz, 1H)), 7.37(app t, J=9.3 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −111.06 (q, J=9.0Hz), −111.78 (q, J=8.8 Hz). LCMS: rt 6.43 min (A), purity 99%, MS (m/e)343 MH⁺.

2-(5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-1-yl)acetamide(Compound 750). ¹H NMR (300 MHz, DMSO-d₆): δ 8.63 (dd, J=4.7, 1.7 Hz,1H), 8.04 (d, J=1.0 Hz, 1H), 7.84 (dd, J=7.8, 1.8 Hz, 1H), 7.65 (s, 1H),7.59-7.51 (m, 1H), 7.50-7.43 (m, 2H), 7.38 (dd, J=8.0, 2.2 Hz, 1H), 7.20(br s, 1H), 7.06 (dd, J=8.7, 1.7 Hz, 1H), 6.99-6.82 (m, 2H), 5.02 (s,2H), 2.13 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.90 (s). LCMS: r4.33 min (A), purity 99%, MS (m/e) 361 MH⁺.

2-(5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl)acetamide(Compound 751). ¹H NMR (300 MHz, DMSO-d₆): δ 8.63 (dd, J=4.7, 1.6 Hz,1H), 8.33 (d, J=0.9 Hz, 1H), 7.83 (dd, J=7.7, 1.7 Hz, 1H), 7.72-7.61 (m,2H), 7.48-7.43 (m, 2H), 7.43-7.40 (m, 1H), 7.36-7.29 (m, 1H), 6.98 (ddd,J=7.7, 5.2, 2.1 Hz, 1H), 6.93 (d, J=9.4 Hz, 1H), 6.87 (dd, J=8.9, 1.6Hz, 1H), 5.07 (s, 2H), 2.15 (s, 3H). LCMS: rt 4.18 min (A), purity 99%,MS (m/e) 361 MH⁺.

2-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-1-yl)acetamide(Compound 752). ¹H NMR (300 MHz, DMSO-d₆): δ 8.66 (dd, J=4.7, 1.7 Hz,1H), 8.03 (d, J=0.9 Hz, 1H), 7.84 (dd, J=7.7, 1.7 Hz, 1H), 7.61 (br s,1H), 7.59 (dd, J=8.3, 0.8 Hz, 1H), 7.47 (dd, J=7.8, 4.7 Hz, 2H), 7.36(dd, J=7.8, 2.2 Hz, 1H), 7.16 (br s, 1H), 6.97 (ddd, J=7.5, 5.3, 2.1 Hz,1H), 6.89 (dd, J=9.6, 8.5 Hz, 1H), 6.76 (dd, J=8.3, 1.4 Hz, 1H), 5.01(s, 2H), 2.21 (s, 3H). LCMS: rt4.55 min (A), purity 99%, MS (m/e) 361MH⁺.

2-(6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-1H-indazol-1-yl)acetamide(Compound 753). LCMS: rt 5.18 min (A), purity 99%, MS (m/e) 381 MH⁺.

2-(6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-2H-indazol-2-yl)acetamide(Compound 754). ¹H NMR (300 MHz, DMSO-d₆): δ 8.65 (dd, J=4.8, 1.6 Hz,1H), 8.30 (s, 1H), 7.87 (dd, J=7.8, 1.7 Hz, 1H), 7.62 (s, 1H), 7.57 (dd,J=8.6, 0.9 Hz, 1H), 7.52 (q, J=1.1 Hz, 1H), 7.51-7.37 (m, 2H), 7.29 (s,1H), 7.01 (ddd, J=7.8, 5.2, 2.4 Hz, 1H), 6.91 (dd, J=9.7, 8.5 Hz, 1H),6.68 (dd, J=8.6, 1.5 Hz, 1H), 5.07 (s, 2H), 2.14 (s 3H). LCMS: rt 4.40min (A), purity 99%, MS (m/e) 361 MH⁺.

2-(6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-2H-indazol-2-yl)acetamide(Compound 755). LCMS: rt 5.01 min (A), purity 99%, MS (m/e) 381 MH⁺.

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Compound 756). LCMS: rt 5.58 min (A), purity 99%, MS (m/e) 304 MH⁺.

5-(2-(m-Tolyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine (Compound 757). LCMS:rt 5.15 min (A), purity 99%, MS (m/e) 286 MH⁺.

5-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Compound 758). LCMS: rt 6.71 min (A), purity 99%, MS (m/e) 324 MH⁺.

5-(2-(3-Chlorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine (Compound759). LCMS: rt 6.28 min (A), purity 99%, MS (m/e) 306 MH⁺.

5-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Compound 760). LCMS: rt 7.48 min (A), purity 99%, MS (m/e) 342 MH⁺.

5-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Compound 761). ¹H NMR (300 MHz, DMSO-d₆): δ 8.73 (dd, J=4.8, 1.6 Hz,1H), 8.56 (dt, J=7.2, 1.0 Hz, 1H), 8.01 (dd, J=7.8, 1.7 Hz, 1H), 7.96(d, J=2.3 Hz, 1H), 7.65-7.57 (m, 2H), 7.56 (dd, J=2.0, 1.0 Hz, 1H), 7.44(ddd, J=8.8, 4.4, 2.8 Hz, 1H), 7.10 (dd, J=9.6, 8.9 Hz, 1H), 6.60 (dd,J=7.2, 2.0 Hz, 1H), 6.57 (dd, J=2.3, 0.9 Hz, 1H). ¹⁹F NMR (282 MHz,DMSO-d₆): δ −117.44 (dt, J=10.1, 5.4 Hz). LCMS: rt 7.13 min (A), purity99%, MS (m/e) 324 MH⁺.

1-(6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one(Compound 762). LCMS: rt 5.58 min (A), purity 99%, MS (m/e) 366 MH⁺.

1-(6-(2-(3-Chlorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one(Compound 763). LCMS: rt 5.21 min (A), purity 99%, MS (m/e) 348 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-methylimidazo[1,2-a]pyridine(Compound 764). LCMS: rt 4.83 min (A), purity 99%, MS (m/e) 338 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)-3-methylimidazo[1,2-a]pyridine(Compound 765). LCMS: rt 4.46 min (A), purity 99%, MS (m/e) 320 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-3-methylimidazo[1,2-a]pyridine(Compound 766). ¹H NMR (300 MHz, DMSO-d₆): δ 8.73 (dd, J=4.8, 1.6 Hz,1H), 8.20 (dd, J=1.8, 1.0 Hz, 1H), 8.07 (dd, J=7.8, 1.6 Hz, 1H), 7.82(dd, J=8.4, 7.4 Hz, 1H), 7.61 (dd, J=7.8, 4.8 Hz, 1H), 7.50-7.28 (m,3H), 6.91 (dd, J=9.3, 1.8 Hz, 1H), 2.37 (s, 3H).). ¹⁹F NMR (282 MHz,DMSO-d₆): δ −111.47 (q, J=9.0 Hz), −111.57 (q, J=8.8 Hz). LCMS: rt 5.10min (A), purity 99%, MS (m/e) 356 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-3-methylimidazo[1,2-a]pyridine(Compound 767). LCMS: rt 4.86 min (A), purity 99%, MS (m/e) 338 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 768). ¹H NMR (300 MHz, DMSO-d₆): δ 8.67 (dd, J=4.7, 1.7 Hz,1H), 8.18 (s, 1H), 7.91 (dd, J=7.8, 1.7 Hz, 1H), 7.60-7.46 (m, 4H),7.28-7.09 (m, 2H), 6.90 (dd, J=8.3, 1.7 Hz, 1H), 3.79 (s, 3H).). ¹⁹F NMR(282 MHz, DMSO-d₆): δ −117.66 (s). LCMS: rt 4.48 min (A), purity 99%, MS(m/e) 338 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 769). LCMS: rt 4.10 min (A), purity 99%, MS (m/e) 320 MH⁺.

6-(2-(3-Chloro-5-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 770). LCMS: rt 6.23 min (A), purity 99%, MS (m/e) 325 MH⁺.

6-(2-(2,5-Dichlorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 771). LCMS: rt 6.30 min (A), purity 99%, MS (m/e) 341 MH⁺.

6-(2-(3-Chloro-2-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 772). LCMS: rt 5.91 min (A), purity 99%, MS (m/e) 325 MH⁺.

6-(2-(3-Chloro-2-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 773). LCMS: rt 5.30 min (A), purity 99%, MS (m/e) 321 MH⁺.

6-(2-(5-Chloro-2-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 774). LCMS: rt 5.75 min (A), purity 99%, MS (m/e) 321 MH⁺.

6-(2-(3-Chloro-5-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 775). LCMS: rt 5.36 min (A), purity 99%, MS (m/e) 321 MH⁺.

6-(2-(3,5-Dichlorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 776). LCMS: rt 6.80 min (A), purity 99%, MS (m/e) 341 MH⁺.

6-(2-(3,4-Dimethylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 777). LCMS: rt 4.63 min (A), purity 99%, MS (m/e) 301 MH⁺.

6-(2-(2,4-Dichlorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 778). LCMS: rt 6.21 min (A), purity 99%, MS (m/e) 341 MH⁺.

6-(2-(3-Methoxyphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 779). ¹H NMR (300 MHz, DMSO-d₆): δ 8.99 (dd, J=1.9, 0.9 Hz,1H), 8.77 (ddd, J=4.9, 1.7, 0.6 Hz, 1H), 8.50 (s, 1H), 8.11 (dt, J=7.8,1.4 Hz, 1H), 7.70 (dd, J=9.3, 0.9 Hz, 1H), 7.61 (ddd, J=7.9, 4.9, 0.9Hz, 1H), 7.29 (ddd, J=9.2, 1.8, 0.6 Hz, 1H), 7.23-7.10 (m, 1H),7.05-6.96 (m, 1H), 6.92-6.83 (m, 2H), 3.62 (s, 3H). LCMS: rt 4.26 min(A), purity 99%, MS (m/e) 303 MH⁺.

6-(2-(3-(Trifluoromethoxy)phenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 780). LCMS: rt 6.23 min (A), purity 99%, MS (m/e) 357 MH⁺.

6-(2-Phenylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (Compound 781).LCMS: rt 3.93 min (A), purity 99%, MS (m/e) 273 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-1H-benzo[d]imidazole(Compound 782). ¹H NMR (300 MHz, DMSO-d₆): δ 8.66 (dd, J=4.7, 1.7 Hz,1H), 8.36 (s, 1H), 7.88 (dd, J=7.8, 1.7 Hz, 1H), 7.60-7.45 (m, 4H),7.27-7.10 (m, 2H), 7.01 (dd, J=8.4, 1.7 Hz, 1H). ¹⁹F NMR (282 MHz,DMSO-d₆): δ −117.47-−117.92 (m). LCMS: rt 4.35 min (A), purity 99%, MS(m/e) 324 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-1H-benzo[d]imidazole(Compound 783). LCMS: rt 4.00 min (A), purity 99%, MS (m/e) 306 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 784). ¹H NMR (300 MHz, DMSO-d₆): δ 8.68 (dd, J=4.7, 1.7 Hz,1H), 8.16 (s, 1H), 7.97 (dd, J=7.8, 1.7 Hz, 1H), 7.74 (dd, J=8.4, 7.3Hz, 1H), 7.58 (dd, J=7.8, 4.8 Hz, 1H), 7.53-7.45 (m, 2H), 7.29 (t, J=9.6Hz, 1H), 6.92 (dd, J=8.3, 1.7 Hz, 1H), 3.76 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆): δ −111.26 (q, J=8.5 Hz), −112.11 (q, J=8.9 Hz). LCMS: rt 5.05min (A), purity 99%, MS (m/e) 356 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 785). LCMS: rt 4.78 min (A), purity 99%, MS (m/e) 338 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-3-amine (Compound786). ¹H NMR (300 MHz, DMSO-d₆): δ 11.33 (s, 1H), 8.63 (dd, J=4.7, 1.7Hz, 1H), 7.82 (dd, J=7.7, 1.7 Hz, 1H), 7.56 (dd, J=8.3, 0.8 Hz, 1H),7.43 (dd, J=7.7, 4.7 Hz, 1H), 7.38 (ddd, J=7.5, 2.2, 1.2 Hz, 1H), 7.05(dd, J=1.4, 0.8 Hz, 1H), 7.02-6.93 (m, 1H), 6.90 (dd, J=9.7, 8.5 Hz,1H), 6.63 (dd, J=8.3, 1.4 Hz, 1H), 5.27 (s, 2H), 2.13 (s, 3H). LCMS: rt4.13 min (A), purity 99%, MS (m/e) 319 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-methyl-1H-indazol-3-amine(Compound 787). LCMS: rt 4.63 min (A), purity 99%, MS (m/e) 333 MH⁺.

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-3-amine (Compound788). LCMS: rt 4.05 min (A), purity 99%, MS (m/e) 319 MH⁺.

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-methyl-1H-indazol-3-amine(Compound 789). LCMS: rt 4.73 min (A), purity 99%, MS (m/e) 333 MH⁺.

(S)-6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(quinuclidin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 790). LCMS: rt 3.81 min (A), purity 99%, MS (m/e) 456 MH⁺.

(R)-6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(quinuclidin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 791). LCMS: rt 3.81 min (A), purity 99%, MS (m/e) 456 MH⁺.

(S)-5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(quinuclidin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 792). LCMS: rt 4.23 min (A), purity 99%, MS (m/e) 456 MH⁺.

(R)-5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(quinuclidin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 793). LCMS: rt 4.23 min (A), purity 99%, MS (m/e) 456 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)benzo[d]isoxazol-3-amine(Compound 794). ¹H NMR (300 MHz, DMSO-d₆): δ 8.67 (dd, J=4.7, 1.7 Hz,1H), 7.87 (dd, J=7.8, 1.7 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.47 (dd,J=7.8, 4.7 Hz, 1H), 7.40-7.25 (m, 2H), 7.02-6.82 (m, 3H), 6.35 (s, 2H),2.13 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −118.64 (app s). LCMS: rt5.11 min (A), purity 99%, MS (m/e) 320 MH⁺.

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)benzo[d]isoxazol-3-amine(Compound 795). LCMS: rt 5.11 min (A), purity 99%, MS (m/e) 320 MH⁺.

5-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)benzo[d]isoxazol-3-amine(Compound 796). LCMS: rt 5.98 min (A), purity 99%, MS (m/e) 340 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)benzo[d]isoxazol-3-amine(Compound 797). LCMS: rt 6.15 min (A), purity 99%, MS (m/e) 340 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)benzo[d]isoxazol-3-amine (Compound798). LCMS: rt 5.76 min (A), purity 99%, MS (m/e) 321 MH⁺.

5-(2-(3-Chlorophenyl)pyridin-3-yl)benzo[d]isoxazol-3-amine (Compound799). LCMS: rt 5.53 min (A), purity 99%, MS (m/e) 322 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-1H-indazol-3-amine (Compound800). LCMS: rt 4.85 min (A), purity 99%, MS (m/e) 339 MH⁺.

5-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-1H-indazol-3-amine (Compound801). LCMS: rt 4.63 min (A), purity 99%, MS (m/e) 339 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 802). LCMS: rt 4.08 min (A), purity 99%, MS (m/e) 470 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(tetrahydro-1H-pyrrolizin-7a(5H)-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 803). LCMS: rt 3.98 min (A), purity 99%, MS (m/e) 484 MH⁺.

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 804). LCMS: rt 4.53 min (A), purity 99%, MS (m/e) 470 MH⁺.

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(tetrahydro-1H-pyrrolizin-7a(5H)-yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide(Compound 805). LCMS: rt 4.38 min (A), purity 99%, MS (m/e) 484 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-4-amine(Compound 806). ¹H NMR (300 MHz, DMSO-d₆): δ 8.73 (app dd, J=4.8, 1.9Hz, 2H), 8.53 (app d, J=2.7 Hz, 2H), 8.15 (s, 2H), 7.99 (dd, J=7.8, 1.7Hz, 1H), 7.56 (dd, J=7.8, 4.8 Hz, 1H), 7.39 (ddt, J=7.7, 2.1, 1.0 Hz,1H), 6.99-6.93 (m, 2H), 2.16 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−118.12 (dd, J=9.1, 6.4 Hz). LCMS: rt 3.76 min (A), purity 99%, MS (m/e)332 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-4-amine(Compound 807). LCMS: rt 4.41 min (A), purity 99%, MS (m/e) 352 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-7-methylimidazo[1,2-a]pyridine(Compound 808). ¹H NMR (300 MHz, DMSO-d₆): δ 8.87 (s, 1H), 8.80 (dd,J=4.8, 1.7 Hz, 1H), 8.21 (dd, J=2.1, 0.7 Hz, 1H), 8.14 (d, J=2.1 Hz,1H), 7.86 (dd, J=7.7, 1.7 Hz, 1H), 7.77 (q, J=1.0 Hz, 1H), 7.56 (dd,J=7.7, 4.8 Hz, 1H), 7.45 (ddd, J=7.6, 2.4, 1.0 Hz, 1H), 7.06 (ddd,J=7.8, 5.0, 2.3 Hz, 1H), 6.94 (dd, J=9.6, 8.5 Hz, 1H), 2.14 (s, 3H),1.96 (app s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.60 (app s). LCMS:rt4.23 min (A), purity 99%, MS (m/e) 318 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 809). LCMS: rt 5.08 min (A), purity 99%, MS (m/e) 319 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 810). ¹H NMR (300 MHz, DMSO-d₆): δ 8.78 (dd, J=4.8, 1.7 Hz,1H), 8.53 (s, 1H), 7.99-7.92 (m, 1H), 7.72 (dd, J=9.2, 0.8 Hz, 1H),7.64-7.55 (m, 2H), 7.45 (d, J=9.1 Hz, 1H), 7.24 (t, J=8.9 Hz, 1H), 7.16(ddd, J=8.6, 4.9, 2.1 Hz, 1H), 2.41 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆):δ −116.72 (app td, J=8.3, 5.1 Hz). LCMS: rt 6.15 min (A), purity 99%, MS(m/e) 339 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 811). LCMS: rt 5.71 min (A), purity 99%, MS (m/e) 321 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 812). LCMS: rt 6.35 min (A), purity 99%, MS (m/e) 339 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 813). LCMS: rt 6.65 min (A), purity 99%, MS (m/e) 357 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 814). ¹H NMR (300 MHz, DMSO-d₆): δ 8.92 (s, 1H), 8.79 (ddd,J=4.9, 1.7, 0.8 Hz, 1H), 8.47 (d, J=0.9 Hz, 1H), 7.97 (ddd, J=7.7, 1.7,0.9 Hz, 1H), 7.67 (q, J=1.0 Hz, 1H), 7.60 (ddd, J=7.7, 4.9, 0.9 Hz, 1H),7.43 (ddd, J=7.6, 2.3, 1.0 Hz, 1H), 7.09 (ddd, J=8.5, 5.1, 2.3 Hz, 1H),6.97 (dd, J=9.7, 8.6 Hz, 1H), 2.12 (s, 3H), 1.92 (s, 3H). ¹⁹F NMR (282MHz, DMSO-d₆): δ −117.35 (app s). LCMS: rt 5.08 min (A), purity 99%, MS(m/e) 319 MH⁺.

N-(2-Acetamidoethyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 815). LCMS: rt 3.93 min (A), purity 99%, MS (m/e) 432 MH⁺.

N-(3-Acetamidopropyl)-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 816). LCMS: rt 4.03 min (A), purity 99%, MS (m/e) 446 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-(2-oxooxazolidin-3-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 817). LCMS: rt 4.16 min (A), purity 99%, MS (m/e) 460 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)quinazolin-4-amine (Compound818). ¹H NMR (300 MHz, DMSO-d₆): δ 8.73 (dd, J=4.8, 1.6 Hz, 1H), 8.34(s, 1H), 8.25-8.18 (m, 1H), 8.00 (dd, J=7.8, 1.7 Hz, 1H), 7.83-7.66 (brs, 2H), 7.66-7.56 (m, 2H), 7.48 (d, J=8.6 Hz, 1H), 7.45-7.35 (m, 2H),7.02 (dd, J=9.6, 8.8 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−117.11-−117.25 (app m). LCMS: rt 4.55 min (A), purity 99%, MS (m/e) 351MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)quinazolin-4-amine(Compound 819). ¹H NMR (300 MHz, DMSO-d₆): δ 8.73 (dd, J=4.8, 1.6 Hz,1H), 8.36 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.01 (dd, J=7.8, 1.7 Hz, 1H),7.80 (dd, J=8.5, 7.3 Hz, 1H), 7.75 (br s, 2H), 7.63 (dd, J=7.8, 4.8 Hz,1H), 7.52 (d, J=8.6 Hz, 1H), 7.43 (dd, J=8.6, 1.9 Hz, 1H), 7.31 (t,J=9.7 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −111.32 (q, J=8.8 Hz),−111.57 (q, J=8.9 Hz). LCMS: rt 4.80 min (A), purity 99%, MS (m/e) 369MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-4-methoxyquinazoline(Compound 820). ¹H NMR (300 MHz, DMSO-d₆): δ 8.78 (s, 1H), 8.75 (dd,J=4.8, 1.6 Hz, 1H), 8.05 (dd, J=8.6, 1.6 Hz 1H), 8.00 (dd, J=2.1, 0.6Hz, 1H), 7.79 (dd, J=8.6, 0.6 Hz, 1H), 7.70-7.58 (m, 3H), 7.42 (ddd,J=8.8, 4.4, 2.8 Hz, 1H), 7.03 (dd, J=9.6, 8.9 Hz, 1H), 4.09 (s, 3H). ¹⁹FNMR (282 MHz, DMSO-d₆): δ −117.61 (ddd, J=10.1, 6.3, 4.4 Hz). LCMS: rt6.91 min (A), purity 99%, MS (m/e) 366 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-4-methoxyquinazoline(Compound 821). ¹H NMR (300 MHz, DMSO-d₆): δ 8.79 (s, 1H), 8.75 (dd,J=4.8, 1.6 Hz, 1H), 8.06 (dd, J=7.8, 1.6 Hz, 1H), 8.01 (dd, J=2.1, 0.6Hz, 1H), 7.86 (d, J=7.4 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.70-7.57 (m,2H), 7.32 (t, J=9.7 Hz, 1H), 4.10 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−111.35 (q, J=8.9 Hz), −111.82 (q, J=8.7 Hz). LCMS: rt 7.26 min (A),purity 99%, MS (m/e) 384 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)quinazolin-4(3H)-one(Compound 822). ¹H NMR (300 MHz, DMSO-d₆): δ 12.25 (br, 1H), 8.73 (dd,J=4.8, 1.6 Hz, 1H), 8.08 (s, 1H), 8.00 (dd, J=7.8, 1.5 Hz, 1H), 7.92(dd, J=1.7, 1.0 Hz, 1H), 7.67-7.53 (m, 4H), 7.42 (ddd, J=8.9, 4.4, 2.8Hz, 1H), 7.06 (dd, J=9.6, 8.8 Hz, 1H). LCMS: rt 5.53 min (A), purity99%, MS (m/e) 352 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)quinazolin-4(3H)-one(Compound 823). ¹H NMR (300 MHz, DMSO-d₆): δ 12.28 (s, 1H), 8.73 (dd,J=4.8, 1.6 Hz, 1H), 8.08 (s, 1H), 8.01 (dd, J=7.8, 1.6 Hz, 1H), 7.93 (t,J=1.4 Hz, 1H), 7.83 (dd, J=8.5, 7.3 Hz, 1H), 7.63-7.59 (m, 1H), 7.58 (d,J=1.4 Hz, 2H), 7.36 (t, J=9.6 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−111.43 (q, J=9.0 Hz), −111.78 (q, J=8.7 Hz). LCMS: rt 5.83 min (A),purity 99%, MS (m/e) 370 MH⁺.

2-(2,3-Dihydro-1H-inden-5-yl)-3,4′-bipyridine (Compound 824). LCMS: rt4.23 min (A), purity 99%, MS (m/e) 273 MH⁺.

6-(2-(2,3-Dihydro-1H-inden-5-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 825). ¹H NMR (300 MHz, DMSO-d₆): δ 9.00 (dd, J=1.8, 0.9 Hz,1H), 8.70 (dd, J=4.8, 1.7 Hz, 1H), 8.50 (s, 1H), 7.97 (dd, J=7.7, 1.7Hz, 1H), 7.68 (dd, J=9.2, 0.9 Hz, 1H), 7.48 (dd, J=7.8, 4.8 Hz, 1H),7.35 (d, J=1.5 Hz, 1H), 7.24 (dd, J=9.2, 1.8 Hz, 1H), 7.05 (d, J=7.9 Hz,1H), 6.99 (dd, J=7.7, 1.6 Hz, 1H), 2.78 (q, J=8.1 Hz, 4H), 1.96 (p,J=7.5 Hz, 2H). LCMS: rt 4.84 min (A), purity 99%, MS (m/e) 313 MH⁺.

6-(2-(2,3-Dihydro-1H-inden-5-yl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(Compound 826). LCMS: rt 5.46 min (A), purity 99%, MS (m/e) 337 MH⁺.

6-(2-(2,3-Dihydro-1H-inden-5-yl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 827). LCMS: rt 3.81 min (A), purity 99%, MS (m/e) 312 MH⁺.

3-(Benzo[d][1,3]dioxol-5-yl)-2-(2,3-dihydro-1H-inden-5-yl)pyridine(Compound 828). LCMS: rt 6.06 min (A), purity 99%, MS (m/e) 316 MH⁺.

4-(2-(2,3-Dihydro-1H-inden-5-yl)pyridin-3-yl)quino lone (Compound 829).LCMS: rt 5.78 min (A), purity 99%, MS (m/e) 323 MH⁺.

6-(2-(2,3-Dihydro-1H-inden-5-yl)pyridin-3-yl)benzo[d]thiazole (Compound830). LCMS: rt 5.68 min (A), purity 99%, MS (m/e) 329 MH⁺.

6-(2-(2,3-Dihydro-1H-inden-5-yl)pyridin-3-yl)quinoxaline (Compound 831).LCMS: rt 5.39 min (A), purity 99%, MS (m/e) 324 MH⁺.

5-([3,4′-Bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one (Compound 832). ¹HNMR (300 MHz, DMSO-d₆): δ 8.76 (dd, J=4.8, 1.7 Hz, 1H), 8.53-8.45 (m,2H), 7.94 (dd, J=7.8, 1.7 Hz, 1H), 7.63-7.52 (m, 2H), 7.48 (dd, J=8.0,0.8 Hz, 1H), 7.24-7.16 (m, 3H), 3.09-2.92 (m, 2H), 2.62 (d, J=11.8 Hz,2H). LCMS: rt 3.61 min (A), purity 99%, MS (m/e) 287 MH⁺.

2-(3-Methyl-1H-inden-6-yl)-3,4′-bipyridine (Compound 833). MeMgBr [2 mL,1.4 M solution in toluene/THF (75:25)] was added to a stirring solutionof 5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one (175 mg) in THF(4 mL) at −78° C. under argon. The reaction was stirred for 30 min andwarmed to room temperature after complete addition of MeMgBr and. After1 h, the complete consumption of5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one to5-([3,4′-bipyridin]-2-yl)-1-methyl-2,3-dihydro-1H-inden-1-ol wasobserved. Subsequently, the reaction was cooled in ice-bath, quenchedwith conc. HCl (5 mL) over a period of 30 min. The cooling was removedand allowed the reaction to warm to temperature. After 4h, the reactionmixture was concentrated, diluted with EtOAc (50 mL) and aq. NaHCO₃solution (15 mL). Aqueous layer was discarded, washed the organic layerwith brine, dried over MgSO₄, filtered, concentrated and purified byflash column chromatography (Combiflash® Companion System® with RediSep®silica gel column 12 g, 30-50-70% EtOAc/hexanes as an eluting solvent)to obtain 2-(3-Methyl-1H-inden-6-yl)-3,4′-bipyridine as an oil. LCMS: rt4.47 min (A), purity 95%, MS (m/e) 285 (MH⁺).

rac-5-([3,4′-Bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-ol (Compound 834).Sodium borohydride (21 mg) was added to a stirring solution of5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one (162 mg) in MeOH (4mL). The reaction mixture was concentrated and quenched with aq. NH₄Cl.The resultant solid was extracted into CH₂Cl₂ (2×20 mL). Combinedorganic layers were stirred over MgSO4, filtered and concentrated. Flashchromatographic purification (Combiflash® Companion System® withRediSep® silica gel column 12 g, 50-75% EtOAc/hexanes as elutingsolvent) providedrac-5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-ol (170 mg) as awhite solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.69 (dd, J=4.8, 1.6 Hz, 1H),8.48 (d, J=6.0 Hz, 2H), 7.85 (dd, J=7.8, 1.7 Hz, 1H), 7.48 (dd, J=7.8,4.7 Hz, 1H), 7.25-7.11 (m, 4H), 7.00 (dd, J=7.8, 1.5 Hz, 1H), 5.29-5.20(m, 1H), 5.00 (q, J=6.4 Hz, 1H), 2.81 (ddd, J=16.0, 8.7, 3.9 Hz, 1H),2.61 (dt, J=15.9, 8.0 Hz, 1H), 2.36-2.21 (m, 1H), 1.74 (dtd, J=12.8,8.2, 6.3 Hz, 1H). LCMS: rt 2.81 min (A), purity 99%, MS (m/e) 289 (MH⁺).

(E/Z)-5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one oxime(Compound 835). 5-([3,4′-Bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one(162 mg), NH₂OH.HCl (55 mg) and NaOAc (84 mg) were stirred and heated at80° C. for 4h in EtOH (3 mL). The reaction mixture was diluted withwater and filtered the solid The solid was washed with water and driedto obtain 130 mg of(E/Z)-5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one oxime as awhite solid. ¹H NMR (300 MHz, DMSO-d₆): δ 10.93 (s, 1H), 8.71 (dd,J=4.7, 1.7 Hz, 1H), 8.50-8.45 (m, 2H), 7.88 (dd, J=7.8, 1.7 Hz, 1H),7.51 (dd, J=7.8, 4.8 Hz, 1H), 7.41-7.33 (m, 2H), 7.23-7.16 (m, 2H), 7.05(dd, J=7.9, 1.6 Hz, 1H), 2.97-2.83 (m, 2H), 2.76 (ddd, J=9.7, 5.3, 2.1Hz, 2H). LCMS: rt 3.56 min (A), purity 99%, MS (m/e) 302 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinolin-4-amine (Compound836). LCMS: rt 3.98 min (A), purity 99%, MS (m/e) 330 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinolin-4-amine (Compound837). ¹H NMR (300 MHz, DMSO-d₆): δ 8.72 (dd, J=4.7, 1.7 Hz, 1H),8.36-8.28 (m, 2H), 7.96 (dd, J=7.8, 1.7 Hz, 1H), 7.73 (d, J=9.9 Hz, 2H),7.66 (d, J=8.7 Hz, 1H), 7.61-7.54 (m, 2H), 7.38 (dt, J=8.8, 1.6 Hz, 1H),7.23 (dd, J=9.3, 8.6 Hz, 1H), 7.13 (ddd, J=8.6, 4.8, 2.2 Hz, 1H), 6.64(dd, J=6.0, 1.3 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.19 (td,J=8.3, 4.9 Hz). LCMS: rt 4.70 min (A), purity 99%, MS (m/e) 350 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-4-methoxyquinoline (Compound838). ¹H NMR (300 MHz, DMSO-d₆): δ 8.72 (d, J=5.2 Hz, 1H), 8.68 (dd,J=4.7, 1.7 Hz, 1H), 8.07 (dd, J=2.1, 0.6 Hz, 1H), 7.92 (dd, J=7.7, 1.7Hz, 1H), 7.77 (dd, J=8.7, 0.6 Hz, 1H), 7.48 (dd, J=7.7, 4.7 Hz, 1H),7.41-7.36 (m, 1H), 7.33 (dd, J=8.7, 2.1 Hz, 1H), 7.03 (d, J=5.3 Hz, 1H),6.98-6.84 (m, 2H), 4.01 (s, 3H), 2.12 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆): δ −118.46-−118.69 (m). LCMS: rt 4.30 min (A), purity 99%, MS(m/e) 345 MI-1′.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-4-methoxyquinoline (Compound839). LCMS: rt 5.08 min (A), purity 99%, MS (m/e) 365 MI-1′.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-4-methoxyquinoline (Compound840). LCMS: rt 5.28 min (A), purity 99%, MS (m/e) 365 MI-1′.

6-(2-(3-Chlorophenyl)pyridin-3-yl)-4-methoxyquinoline (Compound 841).LCMS: rt 4.76 min (A), purity 99%, MS (m/e) 347 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-4-methoxyquinoline(Compound 842). LCMS: rt 5.52 min (A), purity 99%, MS (m/e) 383 MI-1′.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 843). Conc. H₂SO₄ was added dropwise to stirring TFA at roomtemperature for 5 min.6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(870 mg) was added all at once to the homogenous solution after fumingsubsided from acid mixture. Additional TFA and conc.H₂SO₄ were addedsuccessively to the heterogeneous reaction mixture. After 6h, thereaction mixture was added to ice/water and stirred. The homogeneoussolution was basified with aq. NaOH (50%). The resultant heterogeneousslurry was filtered and dried. Subsequently, the white solid waspurified by flash chromatography (Combiflash® companion System® withRediSep® silica gel column 24 g, 70% EtOAc/hexanes-3% MeOH/EtOH) toobtain6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(720 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 9.48 (s, 1H), 8.72 (dd, J=4.8,1.6 Hz, 1H), 8.33 (s, 1H), 7.97 (dd, J=7.8, 1.7 Hz, 2H), 7.64 (d, J=6.8Hz, 1H), 7.61-7.57 (m, 1H), 7.55 (dd, J=7.9, 4.9 Hz, 1H), 7.52-7.48 (brs, 2H), 7.26 (dd, J=7.7, 1.5 Hz, 1H), 7.10 (dd, J=9.4, 1.9 Hz, 1H). ¹⁹FNMR (282 MHz, DMSO-d₆): δ −117.01 (q, J=7.5, 7.1 Hz). LCMS: rt 4.65 min(A), purity 99%, MS (m/e) 367 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyridine(Compound 844).6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(290 mg) and DMF.DMA (5 mL) were heated at 95° C. and stirred in a screwcapped vial overnight. The pale yellow homogeneous reaction mixture wascooled to room temperature and concentrated the heterogeneous slurry byrotary evaporator under vacuum. The off-white solid residue wastransferred to a screw capped vial, treated with AcOH (3 mL) dropwisefor 3 min followed by N₂H₄.H₂O (0.05 mL) and heated for 1 h at 90° C.The homogeneous reaction mixture was concentrated, diluted withice/water and allowed the resulting suspension warm to room temperature.Upon filtration, the collected solid was neutralized with aq. NaHCO₃ andfiltered again to obtain6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-3-(1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyridineas an off-white solid (220 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 14.03 (brs, 1H), 9.46 (dd, J=1.9, 1.0 Hz, 1H), 8.79-8.70 (m, 1H), 8.70-8.52 (m,1H), 8.18 (s, 1H), 8.02 (dd, J=7.8, 1.6 Hz, 1H), 7.67 (dd, J=6.2, 1.4Hz, 1H), 7.61 (dd, J=9.3, 1.0 Hz, 1H), 7.56 (dd, J=7.8, 4.7 Hz, 1H),7.28 (d, J=0.7 Hz, 1H), 7.27-7.20 (m, 1H), 7.04 (dd, J=9.3, 1.8 Hz, 1H).¹⁹F NMR (282 MHz, DMSO-d₆): δ −114.49-−119.56 (m). LCMS: rt 4.70 min(A), purity 99%, MS (m/e) 391 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1H-imidazol-2-yl)imidazo[1,2-a]pyridine(Compound 845). Aminoacetaldeyde (0.2 mL, 0.193 g, 1.72 mmol) was addedto dry THF (8 mL) under argon and cooled the homogenous solution to −78°C. and stirred for 5 min. n-BuLi (1.2 mL, 1.6 M solution in hexanes,1.97 mmol) was added dropwise for 10 min and stirred for 30 min.6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(0.3 g, 0.86 mmol) dissolved in dry THF (5 mL) was added to the abovefaint yellow homogeneous solution. The red solution was cooled andstirred at 0° C. for 2h. Subsequently, dark reaction mixture wasconcentrated under vacuum by rotary evaporator, treated with 6N aq. HCl(15 mL), stirred and heated at 90° C. for 2h. The reaction mixture wasconcentrated, neutralized with aq. NaOH and extracted into CH₂Cl₂.Workup and purification by preparative HPLC provided(6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile(120 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 12.70 (s, 1H), 9.73 (s, 1H), 8.73(dd, J=4.7, 1.5 Hz, 1H), 8.14 (s, 1H), 8.00 (dd, J=7.8, 1.6 Hz, 1H),7.67 (d, J=6.4 Hz, 1H), 7.62-7.50 (m, 3H), 7.34-7.18 (m, 3H), 7.02 (dd,J=9.3, 1.9 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.11 (q, J=7.3 Hz).LCMS: rt 4.81 min (A), purity 99%, MS (m/e) 390 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinoline-4-carboxamide(Compound 846). ¹H NMR (300 MHz, DMSO-d₆): δ 8.99 (d, J=4.4 Hz, 1H),8.76 (dd, J=5.0, 1.6 Hz, 1H), 8.24 (t, J=2.2 Hz, 2H), 8.09 (dd, J=7.8,1.6 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.90 (s, 2H), 7.71-7.58 (m, 2H),7.44 (ddd, J=11.6, 8.1, 2.0 Hz, 2H), 7.06-6.87 (m, 1H), 2.14 (d, J=1.9Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.44 (s). LCMS: rt 4.11 min(A), purity 99%, MS (m/e) 358 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinoline-4-carboxamide(Compound 847). LCMS: rt 4.76 min (A), purity 99%, MS (m/e) 378 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)quinoline-4-carboxamide (Compound848). LCMS: rt 4.36 min (A), purity 99%, MS (m/e) 360 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)quinoline-4-carboxamide(Compound 849). LCMS: rt 4.86 min (A), purity 99%, MS (m/e) 378 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)quinoline-4-carboxamide(Compound 850). LCMS: rt 5.20 min (A), purity 99%, MS (m/e) 396 MH⁺.

7-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine(Compound 851). ¹H NMR (300 MHz, DMSO-d₆): δ 9.20 (t, J=0.8 Hz, 1H),8.76 (ddd, J=4.8, 1.6, 0.6 Hz, 1H), 8.47 (dt, J=7.2, 0.9 Hz, 1H), 8.05(ddd, J=7.9, 1.7, 0.6 Hz, 1H), 7.70-7.59 (m, 3H), 7.46 (dddd, J=8.9,4.3, 2.8, 0.6 Hz, 1H), 7.11 (ddd, J=9.5, 8.8, 0.6 Hz, 1H), 6.76 (ddd,J=7.1, 1.6, 0.6 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −115.57-−119.56(m). LCMS: rt 5.00 min (A), purity 99%, MS (m/e) 325 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine(Compound 852).1-(6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one(300 mg) and DMF.DMA (5 mL) were heated at 95° C. and stirred in a screwcapped vial overnight. The reaction mixture was concentrated and thesemi-solid residue was diluted with Et₂O/hexanes (1:1). The solid wasfiltered and dried. The enamine (75 mg) and the hydrazine (1.2 eq) wereheated in a screw capped vial at 100° C. for 12 h. The reaction mixturewas concentrated and purified by preparative HPLC. ¹H NMR (300 MHz,DMSO-d₆): δ 13.02 (br s), 9.71 (dd, J=1.8, 1.0 Hz, 1H), 8.79 (dd, J=4.8,1.6 Hz, 1H), 8.62 (s, 1H), 8.06 (dd, J=7.8, 1.7 Hz, 1H), 8.01 (d, J=2.4Hz, 1H), 7.89 (dd, J=9.3, 0.9 Hz, 1H), 7.74 (dd, J=7.3, 2.1 Hz, 1H),7.62 (dd, J=7.8, 4.8 Hz, 1H), 7.50 (dd, J=9.3, 1.7 Hz, 1H), 7.37-7.14(m, 2H), 6.95 (d, J=2.4 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −116.76(q, J=7.3 Hz). LCMS: rt 4.98 min (A), purity 99%, MS (m/e) 390 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridine(Compound 853).6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridinewas prepared by the reaction of MeNHNH₂ and enamine, analogous to thepreparation of6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-3-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine.¹H NMR (300 MHz, DMSO-d₆): δ 8.74 (dd, J=4.8, 1.6 Hz, 1H), 8.43 (dd,J=1.7, 0.9 Hz, 1H), 8.42 (s, 1H), 8.04 (dd, J=7.8, 1.6 Hz, 1H), 7.89(dd, J=9.4, 0.8 Hz, 1H), 7.73 (dt, J=8.1, 1.1 Hz, 1H), 7.67 (d, J=2.0Hz, 1H), 7.56 (dd, J=7.8, 4.8 Hz, 1H), 7.51 (dd, J=9.3, 1.6 Hz, 1H),7.31-7.21 (m, 2H), 6.74 (d, J=2.0 Hz, 1H), 3.82 (s, 3H). ¹⁹F NMR (282MHz, DMSO-d₆): δ −116.76 (q, J=7.3 Hz). LCMS: rt 5.09 min (A), purity99%, MS (m/e) 404 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)-5-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 854). LCMS: rt 5.78 min (A), purity 99%, MS (m/e) 335 MH⁺.

7-(2-(3-Chlorophenyl)-5-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 855). ¹H NMR (300 MHz, DMSO-d₆): δ 8.85 (dd, J=7.1, 0.9 Hz,1H), 8.52 (s, 1H), 8.47 (d, J=2.8 Hz, 1H), 7.94-7.89 (m, 1H), 7.62 (d,J=2.8 Hz, 1H), 7.45 (t, J=1.9 Hz, 1H), 7.32 (ddd, J=8.0, 2.2, 1.2 Hz,1H), 7.22 (t, J=7.8 Hz, 1H), 7.12 (dt, J=7.7, 1.4 Hz, 1H), 6.85 (dd,J=7.1, 1.9 Hz, 1H), 3.94 (s, 3H). LCMS: rt 6.40 min (A), purity 99%, MS(m/e) 337 MH⁺.

7-(2-(3-Chloro-4-fluorophenyl)-5-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 856). LCMS: rt 6.75 min (A), purity 99%, MS (m/e) 355 MH⁺.

7-(2-(5-Chloro-2,4-difluorophenyl)-5-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 857). LCMS: rt 6.71 min (A), purity 99%, MS (m/e) 373 MH⁺.

7-(2-(5-Chloro-2-fluorophenyl)-5-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 858). LCMS: rt 6.71 min (A), purity 99%, MS (m/e) 355 MH⁺.

7-(2-(3-(Difluoro-13-methyl)-12-fluoranyl)phenyl)-5-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 859). LCMS: rt 7.05 min (A), purity 99%, MS (m/e) 372 MH⁺.

7-(2-(3-Chloro-4-fluorophenyl)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 860). ¹H NMR (300 MHz, DMSO-d₆): δ 8.87 (dd, J=7.0, 0.9 Hz,1H), 8.77 (d, J=2.8 Hz, 1H), 8.53 (s, 1H), 8.07 (dd, J=9.3, 2.8 Hz, 1H),7.93 (dd, J=1.9, 0.9 Hz, 1H), 7.64 (dd, J=7.3, 2.2 Hz, 1H), 7.28 (dd,J=9.3, 8.6 Hz, 1H), 7.19 (ddd, J=8.6, 4.9, 2.2 Hz, 1H), 6.88 (dd, J=7.1,1.9 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −116.71 (ddd, J=9.4, 7.3, 4.8Hz), −129.02 (d, J=9.2 Hz). LCMS: rt 7.28 min (A), purity 99%, MS (m/e)343 MH⁺.

7-(2-(5-Chloro-2,4-difluorophenyl)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 861). LCMS: rt 7.30 min (A), purity 99%, MS (m/e) 361 MH⁺.

7-(2-(5-Chloro-2-fluorophenyl)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 862). LCMS: rt 7.08 min (A), purity 99%, MS (m/e) 343 MH⁺.

7-(2-(3-((Difluoro-13-methyl)-12-fluoranyl)phenyl)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 863). LCMS: rt 7.55 min (A), purity 99%, MS (m/e) 370 MH⁺.

7-(2-(3-Chloro-4-fluorophenyl)-5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 864). ¹H NMR (300 MHz, DMSO-d₆): δ 8.85 (dd, J=7.0, 0.9 Hz,1H), 8.60 (d, J=1.8 Hz, 1H), 8.52 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H),7.65 (dd, J=7.3, 2.1 Hz, 1H), 7.27 (t, J=8.9 Hz, 1H), 7.19 (ddd, J=8.5,4.9, 2.2 Hz, 1H), 6.85 (dd, J=7.1, 1.8 Hz, 1H), 2.42 (s, 3H). ¹⁹F NMR(282 MHz, DMSO-d₆): δ −116.87 (dd, J=7.6, 3.3 Hz). LCMS: rt 5.86 min(A), purity 99%, MS (m/e) 339 MH⁺.

7-(2-(5-Chloro-2,4-difluorophenyl)-5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 865). LCMS: rt 6.65 min (A), purity 99%, MS (m/e) 357 MH⁺.

7-(2-(5-Chloro-2-fluorophenyl)-5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 866). LCMS: rt 6.25 min (A), purity 99%, MS (m/e) 339 MH⁺.

7-(2-(3-((Difluoro-13-methyl)-12-fluoranyl)phenyl)-5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 867). LCMS: rt 6.26 min (A), purity 99%, MS (m/e) 356 MH⁺.

7-(2-(3-Chlorophenyl)-5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 868). LCMS: rt 5.30 min (A), purity 99%, MS (m/e) 321 MH⁺.

6-(2-(2,5-Dichlorophenyl)pyridin-3-yl)benzo[d]thiazole (Compound 869).¹H NMR (300 MHz, DMSO-d₆): δ 9.37 (s, 1H), 8.70 (dd, J=4.8, 1.6 Hz, 1H),8.05 (dd, J=1.8, 0.6 Hz, 1H), 7.99 (dd, J=7.8, 1.6 Hz, 1H), 7.94 (dd,J=8.4, 0.6 Hz, 1H), 7.60 (dd, J=7.8, 4.8 Hz, 1H), 7.54 (dd, J=2.5, 0.6Hz, 1H), 7.39 (dd, J=8.6, 2.4 Hz, 1H), 7.34 (dd, J=8.6, 0.6 Hz, 1H),7.26 (dd, J=8.5, 1.8 Hz, 1H). LCMS: rt 7.38 min (A), purity 99%, MS(m/e) 356 MH⁺.

6-(2-(2,5-Dichlorophenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 870). ¹H NMR (300 MHz, DMSO-d₆): δ 8.67 (dd, J=4.8, 1.6 Hz,1H), 8.33 (s, 1H), 7.98 (dd, J=7.8, 1.6 Hz, 1H), 7.59 (dd, J=7.9, 4.7Hz, 1H), 7.54-7.48 (m, 3H), 7.41-7.30 (m, 2H), 6.99 (dd, J=8.4, 1.7 Hz,1H), 3.75 (s, 3H). LCMS: rt 4.81 min (A), purity 99%, MS (m/e) 354 MH⁺.

6-(2-(2,5-Dichlorophenyl)pyridin-3-yl)-1H-benzo[d]imidazole (Compound871). LCMS: rt 4.61 min (A), purity 99%, MS (m/e) 340 MH⁺.

6-(2-(2,5-Dichlorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine (Compound872). LCMS: rt 4.70 min (A), purity 99%, MS (m/e) 340 MH⁺.

7-(2-(2,5-Dichlorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 873). LCMS: rt 6.21 min (A), purity 99%, MS (m/e) 341 MH⁺.

7-(2-(2,4,5-Trifluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 874). 17LCMS: rt 5.88 min (A), purity 99%, MS (m/e) 327 MH⁺.

7-(2-(3,4,5-Trifluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 875). LCMS: rt 6.15 min (A), purity 99%, MS (m/e) 327 MH⁺.

7-(2-(2-Chloro-5-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 876). LCMS: rt 6.40 min (A), purity 99%, MS (m/e) 321 MH⁺.

7-(2-(4,5-Difluoro-2-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 877). LCMS: rt 5.31 min (A), purity 99%, MS (m/e) 323 MH⁺.

7-(2-(2-Methyl-5-(trifluoromethyl)phenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 878). LCMS: rt 6.18 min (A), purity 99%, MS (m/e) 355 MH⁺.

7-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 879). LCMS: rt 6.20 min (A), purity 99%, MS (m/e) 341 MH⁺.

7-(2-(3-Methoxyphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 880). ¹H NMR (300 MHz, DMSO-d₆): δ 8.87-8.74 (m, 2H), 8.51 (d,J=1.3 Hz, 1H), 8.15 (dd, J=7.8, 1.6 Hz, 1H), 7.84 (dd, J=2.1, 1.1 Hz,1H), 7.67 (dd, J=7.8, 5.0 Hz, 1H), 7.18 (t, J=7.9 Hz, 1H), 7.02 (dt,J=2.8, 1.5 Hz, 1H), 6.95-6.80 (m, 3H), 3.62 (s, 3H). LCMS: rt 4.28 min(A), purity 99%, MS (m/e) 303 MH⁺.

7-(2-(5-Chloro-2-methoxyphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 881). LCMS: rt 4.98 min (A), purity 99%, MS (m/e) 337 MH⁺.

7-(2-(3-(Trifluoromethoxy)phenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 882). LCMS: rt 6.28 min (A), purity 99%, MS (m/e) 357 MH⁺.

7-(2-(3-(Difluoromethoxy)phenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 883). ¹H NMR (300 MHz, DMSO-d₆): δ 8.83 (dd, J=7.0, 1.0 Hz,1H), 8.78 (dd, J=4.8, 1.6 Hz, 1H), 8.51 (s, 1H), 8.09 (dd, J=7.8, 1.6Hz, 1H), 7.84 (dd, J=2.0, 1.0 Hz, 1H), 7.62 (ddd, J=7.8, 4.8, 0.8 Hz,1H), 7.32 (t, J=7.6 Hz, 1H), 7.24-7.07 (m, 4H), 6.85 (dd, J=7.1, 1.9 Hz,1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −82.56 (d, J=73.8 Hz). LCMS: rt 5.36min (A), purity 99%, MS (m/e) 339 MH⁺.

7-(2-(2-Fluoro-5-(trifluoromethoxy)phenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 884). LCMS: rt 6.83 min (A), purity 99%, MS (m/e) 375 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl-1-oxy)quinazolin-4-amine(Compound 885).4-Chloro-6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)quinazoline (75 mg),EtOH, 4-amino-2,2,6,6-tetramethyl-1-piperidinyloxy and i-Pr₂NEt wereadded successively to a screw capped vial, stirred and heated at 90° C.for 3 days. The reaction mixture was concentrated and purified bypreparative HPLC to obtain pale pink solid. LCMS: rt 5.85 min (A),purity 99%, MS (m/e) 505 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N-methylquinazolin-4-amine(Compound 886).4-Chloro-6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)quinazoline (75 mg),2M MeNH₂ in THF (2 mL) and i-PrOH (3 mL) were heated and stirred in ascrew capped vial for 12h at 65° C. The heterogeneous reaction mixturewas cooled and filtered. The solid on the funnel was washed with waterand dried to obtain6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-N-methylquinazolin-4-amine(53 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.72 (dd, J=4.7,1.7 Hz, 1H), 8.47 (s, 1H), 8.31 (q, J=4.7 Hz, 1H), 8.25 (d, J=1.9 Hz,1H), 7.95 (dd, J=7.8, 1.7 Hz, 1H), 7.61-7.50 (m, 3H), 7.36 (dd, J=8.6,1.9 Hz, 1H), 7.24 (t, J=8.9 Hz, 1H), 7.13 (ddd, J=8.6, 4.8, 2.2 Hz, 1H),2.98 (d, J=4.4 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.17 (td,J=8.6, 5.1 Hz). LCMS: rt 4.68 min (A), purity 99%, MS (m/e) 365 MH⁺.

7-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-1-methylquinoxalin-2(1H)-one(Compound 887). ¹H NMR (300 MHz, DMSO-d₆): δ 8.73 (dd, J=4.8, 1.6 Hz,1H), 8.30-8.18 (m, 1H), 8.01 (dt, J=7.8, 1.4 Hz, 1H), 7.71 (d, J=8.3 Hz,1H), 7.62 (dt, J=7.3, 1.5 Hz, 1H), 7.60-7.51 (m, 2H), 7.25 (t, J=8.9 Hz,1H), 7.16 (ddd, J=8.4, 4.8, 2.1 Hz, 1H), 7.07 (dd, J=8.3, 1.7 Hz, 1H),3.53 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.11 (td, J=8.6, 5.1 Hz).LCMS: rt 6.26 min (A), purity 99%, MS (m/e) 366 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-1-methylquinoxalin-2(1H)-one(Compound 888). LCMS: rt 5.16 min (A), purity 99%, MS (m/e) 346 MH⁺.

7-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-1-methylquinoxalin-2(1H)-one(Compound 889). LCMS: rt 6.66 min (A), purity 99%, MS (m/e) 366 MH⁺.

7-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)quinoxalin-2(1H)-one(Compound 890). LCMS: rt 5.63 min (A), purity 99%, MS (m/e) 352 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)quinoxalin-2(1H)-one(Compound 891). LCMS: rt 4.73 min (A), purity 99%, MS (m/e) 332 MH⁺.

7-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)quinoxalin-2(1H)-one(Compound 892). ¹H NMR (300 MHz, DMSO-d₆): δ 12.35 (s, 1H), 8.69 (dd,J=4.8, 1.6 Hz, 1H), 8.08 (s, 1H), 7.90 (dd, J=7.9, 1.6 Hz, 1H), 7.64 (d,J=8.8 Hz, 1H), 7.60-7.46 (m, 2H), 7.46-7.30 (m, 1H), 7.15-6.92 (m, 3H).¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.11-−117.91 (m). LCMS: rt 5.93 min(A), purity 99%, MS (m/e) 352 MH⁺.

7-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-2H-benzo[e][1,2,4]thiadiazine1,1-dioxide (Compound 893). LCMS: rt 5.53 min (A), purity 99%, MS (m/e)388 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-2H-benzo[e][1,2,4]thiadiazine1,1-dioxide (Compound 894). LCMS: rt 4.50 min (A), purity 97%, MS (m/e)368 MH⁺.

7-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-2H-benzo[e][1,2,4]thiadiazine1,1-dioxide (Compound 895). ¹H NMR (300 MHz, DMSO-d₆): δ 12.35 (s, 1H),8.69 (dd, J=4.8, 1.6 Hz, 1H), 8.08 (s, 1H), 7.90 (dd, J=7.9, 1.6 Hz,1H), 7.64 (d, J=8.8 Hz, 1H), 7.60-7.50 (m, 2H), 7.39 (ddd, J=8.7, 4.4,2.9 Hz, 1H), 7.11-6.91 (m, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−117.44-−117.69 (m). LCMS: rt 5.86 min (A), purity 97%, MS (m/e) 388MH⁺.

5-(2-(3-Cyclopropyl-4-fluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 896). LCMS: rt 6.03 min (A), MS (m/e) 331 MH⁺.

Ethyl5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(Compound 897). ¹H NMR (300 MHz, DMSO-d₆) δ 8.86 (ddd, J=4.8, 1.7, 0.6Hz, 1H), 8.81 (dd, J=4.4, 0.6 Hz, 1H), 8.44 (s, 1H), 8.12 (ddd, J=7.8,1.7, 0.6 Hz, 1H), 7.61 (dd, J=7.7, 4.7 Hz, 1H), 7.38-7.25 (m, 2H),6.94-6.85 (m, 2H), 4.27 (q, J=7.0 Hz, 2H), 2.08 (s, 3H), 1.29 (t, J=7.0Hz, 3H). LCMS: rt6.88 min (A), purity 99%, MS (m/e) 376 MH⁺.

Ethyl5-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(Compound 898). ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (d, J=7.2 Hz, 1H), 8.82(dd, J=4.7, 1.7 Hz, 1H), 8.62 (s, 1H), 8.21 (dd, J=7.8, 1.7 Hz, 1H),7.73 (dd, J=7.3, 2.2 Hz, 1H), 7.64 (dd, J=7.9, 4.8 Hz, 1H), 7.28 (t,J=8.9 Hz, 1H), 7.23-7.16 (m, 1H), 7.00 (d, J=7.3 Hz, 1H), 4.25 (q, J=7.1Hz, 2H), 1.97 (s, 1H), 1.27 (t, J=7.1 Hz, 3H). LCMS: rt 7.38 min (A),purity 95%, MS (m/e) 397 MH⁺.

5-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-N-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound 899). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (d, J=7.3 Hz, 1H), 8.83(dd, J=4.8, 1.7 Hz, 1H), 8.55 (s, 1H), 8.27 (dd, J=7.9, 1.7 Hz, 1H),7.76 (dd, J=7.2, 2.2 Hz, 1H), 7.66 (dd, J=7.8, 4.8 Hz, 1H), 7.58 (d,J=7.7 Hz, 1H), 7.28 (t, J=8.9 Hz, 1H), 7.12 (d, J=7.3 Hz, 1H), 3.86-3.66(m, 1H), 2.67 (d, J=11.7 Hz, 2H), 2.21-2.14 (m, 5H), 1.77 (d, J=13.1 Hz,2H), 1.52-1.33 (m, 2H). LCMS: rt 3.48 min (B), purity 97%, MS (m/e) 465MH⁺.

5-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(Compound 900). ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (dd, J=7.3, 2.6 Hz,1H), 8.89-8.77 (m, 2H), 8.31-8.17 (m, 1H), 7.79-7.71 (m, 1H), 7.69-7.59(m, 1H), 7.29 (t, J=8.9 Hz, 1H), 7.24-7.14 (m, 1H), 7.04 (dd, J=7.3, 2.7Hz, 1H). LCMS: rt7.05 min (B), purity 99%, MS (m/e) 350 MH⁺.

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(Compound 901). ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (d, J=7.3 Hz, 1H),8.86-8.76 (m, 2H), 8.21 (dd, J=7.9, 1.7 Hz, 1H), 7.66-7.53 (m, 3H),7.06-6.98 (m, 1H), 6.87 (d, J=7.3 Hz, 1H), 2.20 (s, 3H). LCMS: rt6.80min (B), purity 99%, MS (m/e) 330 MH⁺

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-2-methoxypyrimidine(Compound 902). ¹H NMR (300 MHz, DMSO-d₆): δ 8.74 (dd, J=4.8, 1.7 Hz,1H), 8.48 (d, J=5.1 Hz, 1H), 8.08 (dd, J=7.8, 1.7 Hz, 1H), 7.54 (dd,J=7.8, 4.8 Hz, 1H), 7.34 (dd, J=7.6, 2.1 Hz, 0H), 7.11-6.98 (m, 2H),6.90 (d, J=5.1 Hz, 1H), 3.77 (s, 3H), 2.18 (app d, J=2.1 Hz, 2H). ¹⁹FNMR (282 MHz, DMSO-d₆): δ −118.09 (q, J=8.0, 7.5 Hz). LCMS: rt5.04 min(B), purity 99%, MS (m/e) 296 (MH⁺).

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine(Compound 903). ¹H NMR (300 MHz, DMSO-d₆): δ 9.58 (s, 1H), 8.73 (dd,J=4.7, 1.7 Hz, 1H), 8.31 (d, J=5.1 Hz, 1H), 8.16-8.08 (m, 1H), 7.53 (dd,J=7.8, 4.7 Hz, 1H), 7.42 (dd, J=7.0, 2.3 Hz, 1H), 7.19 (s, 2H),7.13-6.99 (m, 2H), 6.45 (d, J=5.0 Hz, 1H), 3.70 (s, 6H), 3.59 (s, 3H),2.19 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.92 (d, J=7.5 Hz). LCMS:rt6.14 min (B), purity 99%, MS (m/e) 447 (MH⁺).

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine(Compound 904). LCMS: rt5.17 min (A), purity 99%, MS (m/e) 442 (MH⁺).

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(3-morpholinophenyl)pyrimidin-2-amine(Compound 905). LCMS: rt5.90 min (A), purity 99%, MS (m/e) 442 (MH⁺).

4-((4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2-yl)amino)benzenesulfonamide(Compound 906). LCMS: rt5.43 min (A), purity 99%, MS (m/e) 436 (MH⁺).

3-((4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2-yl)amino)benzenesulfonamide(Compound 907). ¹H NMR (300 MHz, DMSO-d₆): δ 10.02 (s, 1H), 8.75 (dd,J=4.8, 1.7 Hz, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 8.11 (dd,J=7.8, 1.7 Hz, 1H), 7.65 (dt, J=6.4, 2.5 Hz, 1H), 7.54 (dd, J=7.8, 4.8Hz, 1H), 7.44 (dd, J=7.3, 2.2 Hz, 1H), 7.40-7.31 (m, 2H), 7.27 (s, 2H),7.17-6.95 (m, 2H), 6.67 (d, J=5.1 Hz, 1H), 2.20 (s, 3H). ¹⁹F NMR (282MHz, DMSO-d₆): δ −117.92. LCMS: rt5.58 min (A), purity 99%, MS (m/e) 436(MH⁺).

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(4-(piperazin-1-yl)phenyl)pyrimidin-2-amine(Compound 908). LCMS: rt4.73 min (A), purity 99%, MS (m/e) 441 (MH⁺).

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrimidin-2-amine(Compound 909). LCMS: rt4.60 min (A), purity 99%, MS (m/e) 442 (MH⁺).

5-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 910). LCMS: rt5.41 min (A), purity 99%, MS (m/e) 305 (MH⁺).

5-(2-(m-Tolyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine (Compound 911). ¹HNMR (300 MHz, DMSO-d₆): δ 8.90 (dd, J=7.3, 0.9 Hz, 1H), 8.76 (dd, J=4.7,1.7 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.12 (dd, J=7.8, 1.7 Hz, 1H), 7.54(dd, J=7.8, 4.8 Hz, 1H), 7.33 (s, 1H), 7.15 (dd, J=3.9, 1.5 Hz, 2H),7.01 (dd, J=5.1, 1.5 Hz, 1H), 6.75 (dd, J=2.3, 0.9 Hz, 1H), 6.53 (d,J=7.3 Hz, 1H), 2.25 (s, 3H). LCMS: rt4.90 min (A), purity 99%, MS (m/e)287 (MH⁺).

5-(2-(3-Cyclopropylphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 912). LCMS: rt5.51 min (A), purity 99%, MS (m/e) 313 (MH⁺).

5-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine.(Compound 913). LCMS: rt6.71 min (A), purity 99%, MS (m/e) 341 (MH⁺).

5-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 914). ¹H NMR (300 MHz, DMSO-d₆): δ 9.00 (d, J=7.2 Hz, 1H),8.79 (dd, J=4.8, 1.7 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.15 (dd, J=7.8,1.7 Hz, 1H), 7.68 (dd, J=7.4, 2.1 Hz, 1H), 7.59 (dd, J=7.9, 4.9 Hz, 1H),7.32 (t, J=8.9 Hz, 1H), 7.25-7.10 (m, 1H), 6.73 (d, J=7.1 Hz, 2H). ¹⁹FNMR (282 MHz, DMSO-d₆): δ −116.52-−116.67 (m). LCMS: rt 6.68 min (A),purity 99%, MS (m/e) 325 (MH⁺).

5-(2-(2,4,5-Trifluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 915). LCMS: rt 6.66 min (A), purity 99%, MS (m/e) 327 (MH⁺).

5-(2-(3-Chlorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine (Compound916). ¹H NMR (300 MHz, DMSO-d₆): δ 8.98 (dd, J=7.3, 0.9 Hz, 1H), 8.79(dd, J=4.8, 1.7 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.15 (dd, J=7.8, 1.7Hz, 1H), 7.64-7.54 (m, 2H), 7.41 (ddd, J=8.0, 2.2, 1.1 Hz, 1H), 7.29 (t,J=7.8 Hz, 1H), 7.16 (dt, J=7.7, 1.4 Hz, 1H), 6.74 (dd, J=2.4, 0.9 Hz,1H), 6.69 (d, J=7.3 Hz, 1H). LCMS: rt 4.16 min (A), purity 99%, MS (m/e)307 (MH⁺).

5-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 917). LCMS: rt 6.86 min (A), purity 99%, MS (m/e) 325 (MH⁺).

5-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 918). LCMS: rt 7.18 min (A), purity 99%, MS (m/e) 343 (MH⁺).

4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2-amine (Compound919). ¹H NMR (300 MHz, DMSO-d₆): δ 8.69 (dd, J=4.7, 1.7 Hz, 1H), 8.07(d, J=5.0 Hz, 1H), 7.93 (dd, J=7.8, 1.7 Hz, 1H), 7.47 (dd, J=7.8, 4.8Hz, 1H), 7.38 (dd, J=7.4, 1.6 Hz, 1H), 7.18-6.95 (m, 2H), 6.70 (s, 2H),6.20 (d, J=5.0 Hz, 1H), 2.19 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−118.16 (q, J=7.7 Hz). LCMS: rt4.40 min (A), purity 99%, MS (m/e) 281MH⁺.

5-(2-(2,5-Dichlorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 920). LCMS: rt 7.06 min (A), purity 99%, MS (m/e) 342 MH⁺.

5-(2-(3-(Difluoromethoxy)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 921). ¹H NMR (300 MHz, DMSO-d₆): δ 8.95 (dd, J=7.3, 0.9 Hz,1H), 8.80 (dd, J=4.7, 1.7 Hz, 1H), 8.22 (s, 1H), 8.14 (dd, J=7.8, 1.7Hz, 1H), 7.59 (dd, J=7.8, 4.8 Hz, 1H), 7.43-7.28 (m, 1H), 7.21 (t, J=2.1Hz, 1H), 7.19-7.11 (m, 3H), 6.73 (dd, J=2.3, 0.9 Hz, 1H), 6.64 (d, J=7.3Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −82.40 (d, J=73.8 Hz). LCMS:rt4.95 min (B), purity 99%, MS (m/e) 338 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine(Compound 922). LCMS: rt4.60 min (A), purity 99%, MS (m/e) 306 (MH⁺).

6-(2-(m-Tolyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (Compound923). LCMS: rt4.13 min (A), purity 99%, MS (m/e) 288 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine(Compound 924). LCMS: rt4.81 min (A), purity 99%, MS (m/e) 314 (MH⁺).

6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine(Compound 925). LCMS: rt5.95 min (A), purity 99%, MS (m/e) 342 (MH⁺).

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyrimidine(Compound 926). LCMS: rt3.75 min (A), purity 99%, MS (m/e) 305 (MH⁺).

6-(2-(m-Tolyl)pyridin-3-yl)imidazo[1,2-a]pyrimidine (Compound 927).LCMS: rt3.25 min (A), purity 99%, MS (m/e) 287 (MH⁺).

6-(2-(3-Cyclopropylphenyl)pyridin-3-yl)imidazo[1,2-a]pyrimidine(Compound 928). LCMS: rt3.96 min (A), purity 99%, MS (m/e) 313 (MH⁺).

6-(2-(3-(Trifluoromethyl)phenyl)pyridin-3-yl)imidazo[1,2-a]pyrimidine(Compound 929). LCMS: rt4.73 min (A), purity 99%, MS (m/e) 341 (MH⁺).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-7-methylimidazo[1,2-a]pyridine(Compound 930). LCMS: rt 4.90 min (A), purity 99%, MS (m/e) 338 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)-7-methylimidazo[1,2-a]pyridine(Compound 931). ¹H NMR (300 MHz, DMSO-d₆): δ 8.87 (d, J=0.8 Hz, 1H),8.84 (dd, J=4.8, 1.7 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H), 8.14 (d, J=2.1 Hz,1H), 7.90 (dd, J=7.7, 1.7 Hz, 1H), 7.80 (s, 1H), 7.61 (dd, J=7.8, 4.8Hz, 1H), 7.53 (t, J=1.9 Hz, 1H), 7.36 (dt, J=7.6, 2.0 Hz, 1H), 7.23 (t,J=7.7 Hz, 1H), 7.18 (dt, J=7.8, 1.6 Hz, 1H), 2.00 (s, 3H). LCMS: rt 4.58min (A), purity 99%, MS (m/e) 320 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-7-methylimidazo[1,2-a]pyridine(Compound 932). LCMS: rt 4.86 min (A), purity 99%, MS (m/e) 338 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-7-methylimidazo[1,2-a]pyridine(Compound 933). LCMS: rt5.11 min (A), purity 99%, MS (m/e) 356 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine(Compound 934). LCMS: rt 4.61 min (A), purity 99%, MS (m/e) 305 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine(Compound 935). ¹H NMR (300 MHz, DMSO-d₆): δ 8.76 (dd, J=4.8, 1.7 Hz,1H), 8.26 (dt, J=1.2, 0.6 Hz, 1H), 8.08 (ddd, J=7.8, 1.7, 0.5 Hz, 1H),7.97 (dt, J=9.4, 0.6 Hz, 1H), 7.76 (dd, J=1.2, 0.5 Hz, 1H), 7.62 (dd,J=7.3, 2.3 Hz, 1H), 7.56 (ddd, J=7.8, 4.8, 0.5 Hz, 1H), 7.25 (dd, J=9.3,8.6 Hz, 1H), 7.14 (dddd, J=8.6, 4.8, 2.2, 0.5 Hz, 1H), 6.89 (dd, J=9.5,0.5 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −116.49 (td, J=8.3, 4.9 Hz).LCMS: rt5.13 min (A), purity 99%, MS (m/e) 325 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine (Compound936). LCMS: rt4.83 min (A), purity 99%, MS (m/e) 307 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine(Compound 937). LCMS: rt5.03 min (A), purity 99%, MS (m/e) 325 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine(Compound 938). LCMS: rt5.28 min (A), purity 99%, MS (m/e) 343 MH⁺.

8-Fluoro-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(Compound 939). LCMS: rt5.45 min (A), purity 99%, MS (m/e) 323 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine(Compound 940). ¹H NMR (300 MHz, DMSO-d₆): δ 8.95 (t, J=1.0 Hz, 1H),8.75 (ddd, J=4.8, 1.7, 0.6 Hz, 1H), 8.61 (d, J=0.6 Hz, 1H), 8.04 (ddd,J=7.8, 1.7, 0.6 Hz, 1H), 7.70 (ddd, J=7.3, 1.9, 0.6 Hz, 1H), 7.58 (ddd,J=7.8, 4.8, 0.6 Hz, 1H), 7.42 (ddd, J=11.1, 1.4, 0.6 Hz, 1H), 7.35-7.17(m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −116.75 (td, J=8.1, 5.6 Hz),−130.02 (d, J=11.2 Hz). LCMS: rt6.55 min (A), purity 99%, MS (m/e) 343MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine(Compound 941). LCMS: rt6.13 min (A), purity 99%, MS (m/e) 325 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine(Compound 942). LCMS: rt 6.75 min (A), purity 99%, MS (m/e) 343 MH⁺.

7-Chloro-6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 943). LCMS: rt 4.56 min (A), purity 99%, MS (m/e) 338 MH⁺.

7-Chloro-6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 944). ¹H NMR (300 MHz, DMSO-d₆): δ 8.99 (d, J=0.8 Hz, 1H),8.82 (dd, J=4.8, 1.7 Hz, 1H), 8.19 (dd, J=1.8, 0.8 Hz, 1H), 8.08 (t,J=0.8 Hz, 1H), 8.04 (t, J=1.4 Hz, 1H), 7.92 (dd, J=7.8, 1.7 Hz, 1H),7.73-7.67 (m, 1H), 7.66-7.56 (m, 1H), 7.26 (app d, J=1.3 Hz, 1H), 7.24(app q, J=1.0 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −116.57 (q, J=7.0Hz). LCMS: rt 5.20 min (A), purity 99%, MS (m/e) 359 MH⁺.

7-Chloro-6-(2-(3-chlorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 945). LCMS: rt 4.91 min (A), purity 99%, MS (m/e) 341 MH⁺.

7-Chloro-6-(2-(5-chloro-2-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine(Compound 946). LCMS: rt5.03 min (A), purity 99%, MS (m/e) 359 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carbonitrile(Compound 947). ¹H NMR (300 MHz, DMSO-d₆): δ 8.78 (ddd, J=4.8, 1.7, 0.8Hz, 1H), 8.55 (s, 1H), 8.15 (dd, J=9.5, 0.9 Hz, 1H), 8.10 (ddd, J=7.8,1.7, 0.8 Hz, 1H), 7.59-7.52 (m, 2H), 7.41 (dd, J=7.7, 2.2 Hz, 1H), 7.08(dd, J=9.5, 0.9 Hz, 1H), 6.95 (dd, J=9.6, 8.5 Hz, 1H), 2.13 (s, 3H). ¹⁹FNMR (282 MHz, DMSO-d₆): δ −117.44 (s). LCMS: rt 5.34 min (B), purity99%, MS (m/e) 330 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carbonitrile(Compound 948). LCMS: rt 5.59 min (B), purity 99%, MS (m/e) 350 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carbonitrile(Compound 949). LCMS: rt 5.43 min (B), purity 99%, MS (m/e) 332 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carbonitrile(Compound 950). LCMS: rt 5.34 min (B), purity 99%, MS (m/e) 350 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carbonitrile(Compound 951). LCMS: rt 5.56 min (B), purity 99%, MS (m/e) 368 MH⁺.

6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-b]pyridazine(Compound 952). LCMS: rt 5.68 min (A), purity 99%, MS (m/e) 306 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-b]pyridazine(Compound 953). ¹H NMR (300 MHz, DMSO-d₆): δ 8.84 (dd, J=4.8, 1.7 Hz,1H), 8.70 (s, 1H), 8.34 (d, J=9.3 Hz, 1H), 8.19 (dd, J=7.8, 1.7 Hz, 1H),7.71 (dd, J=7.2, 2.1 Hz, 1H), 7.65 (dd, J=7.8, 4.8 Hz, 1H), 7.39 (d,J=9.4 Hz, 1H), 7.28 (dd, J=9.3, 8.5 Hz, 1H), 7.19 (ddd, J=8.6, 4.8, 2.2Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −116.26 (ddd, J=9.3, 7.3, 4.7Hz). LCMS: rt 6.50 min (A), purity 99%, MS (m/e) 326 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-b]pyridazine(Compound 954). LCMS: rt 6.15 min (A), purity 99%, MS (m/e) 308 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-b]pyridazine(Compound 955). LCMS: rt 6.46 min (A), purity 99%, MS (m/e) 326 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-b]pyridazine(Compound 956). LCMS: rt 6.85 min (A), purity 99%, MS (m/e) 344 MH⁺.

7-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-2-methyl-2H-benzo[e][1,2,4]thiadiazine1,1-dioxide (Compound 957). LCMS: rt 5.91 min (A), purity 97%, MS (m/e)402 MH⁺.

7-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)-2-methyl-2H-benzo[e][1,2,4]thiadiazine1,1-dioxide (Compound 958). ¹H NMR (300 MHz, DMSO-d₆): δ 8.71 (dd,J=4.8, 1.6 Hz, 1H), 8.05 (s, 1H), 7.97 (dd, J=7.8, 1.6 Hz, 1H), 7.68 (d,J=2.1 Hz, 1H), 7.61-7.50 (m, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.37 (ddt,J=7.5, 1.9, 0.8 Hz, 1H), 7.06-6.94 (m, 2H), 3.59 (s, 3H), 2.17 (s, 3H).¹⁹F NMR (282 MHz, DMSO-d₆): δ −117.82 (app s). LCMS: rt4.85 min (A),purity 98%, MS (m/e) 382 MH⁺.

7-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-2-methyl-2H-benzo[e][1,2,4]thiadiazine1,1-dioxide (Compound 959). LCMS: rt6.31 min (A), purity 98%, MS (m/e)402 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4(3H)-one(Compound 960). ¹H NMR (300 MHz, DMSO-d₆): δ 12.60 (s, 1H), 8.77 (appddd, J=4.8, 1.7, 0.6 Hz, 1H), 8.16 (s, 1H), 8.10 (app ddd, J=7.8, 1.8,0.7 Hz, 1H), 7.94 (dd, J=8.6, 0.7 Hz, 1H), 7.65-7.55 (m, 2H), 7.48 (dd,J=8.5, 0.6 Hz, 1H), 7.27 (app t, J=9.0 Hz, 1H), 7.16-7.03 (m, 1H). ¹⁹FNMR (282 MHz, DMSO-d₆): δ −116.85 (app td, J=9.0, 8.5, 4.9 Hz). LCMS:rt4.73 min (A), purity 99%, MS (m/e) 353 MH⁺.

6-(2-(3-(Difluoromethoxy)phenyl)pyridin-3-yl)benzo[d]thiazole (Compound961). LCMS: rt5.67 min (A), purity 97%, MS (m/e) 355 MH⁺.

6-(2-(3-(Difluoromethoxy)phenyl)pyridin-3-yl)quinoxaline (Compound 962).LCMS: rt5.23 min (B), purity 96%, MS (m/e) 350 MH⁺.

6-(2-(3-(Difluoromethoxy)phenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 963). LCMS: rt2.89 min (B), purity 99%, MS (m/e) 352 MH⁺.

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine(Compound 964). ¹H NMR (300 MHz, DMSO-d₆): δ 8.77 (dd, J=4.7, 1.7 Hz,1H), 8.40 (s, 1H), 8.27 (dd, J=7.8, 1.7 Hz, 1H), 7.94 (app d, J=8.7 Hz,2H), 7.69-7.54 (m, 3H), 7.52 (d, J=8.7 Hz, 1H), 7.27 (dd, J=9.3, 8.6 Hz,1H), 7.11 (ddd, J=8.6, 4.7, 2.2 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−116.92 (ddd, J=9.3, 7.3, 4.7 Hz). LCMS: rt4.61 min (A), purity 99%, MS(m/e) 352 MH⁺.

5-(2-(3-Chloro-2,4-difluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine(Compound 965). ¹H NMR (300 MHz, DMSO-d₆): δ 9.05 (dd, J=7.3, 1.0 Hz,1H), 8.82 (dd, J=4.8, 1.7 Hz, 1H), 8.27 (dd, J=7.9, 1.6 Hz, 1H), 8.21(d, J=2.3 Hz, 1H), 7.67 (dd, J=7.8, 4.7 Hz, 1H), 7.55 (td, J=8.5, 6.3Hz, 1H), 7.39 (td, J=8.8, 1.6 Hz, 1H), 6.89 (dd, J=7.3, 1.0 Hz, 1H),6.62 (dd, J=2.3, 0.9 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −113.03(ddd, J=9.3, 6.3, 3.6 Hz), −115.55 (dd, J=9.1, 3.3 Hz). LCMS: rt5.27 min(B), purity 99%, MS (m/e) 343 MH⁺.

6-(2-(3-Chloro-2,4-difluorophenyl)pyridin-3-yl)quinoxaline (Compound966). LCMS: rt5.63 min (B), purity 99%, MS (m/e) 354 MH⁺.

6-(2-(3-Chloro-2,4-difluorophenyl)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole(Compound 967). LCMS: rt3.37 min (B), purity 99%, MS (m/e) 356 MH⁺.

6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine(Compound 968). ¹H NMR (300 MHz, DMSO-d₆): δ 8.86 (s, 1H), 8.80 (dd,J=4.7, 1.7 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.17 (d, J=8.8, 1.7 Hz, 1H),7.77-7.46 (m, 3H), 7.22 (app t, J=9.2 Hz, 1H), 7.07 (ddd, J=8.6, 4.7,2.2 Hz, 1H), 4.15 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −116.74 (ddd,J=9.2, 7.2, 4.7 Hz).

6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 969). LCMS: rt 6.15 min (A), purity 99%, MS (m/e) 339 MH⁺.

6-(2-(3-Chlorophenyl)pyridin-3-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 970). LCMS: rt 5.71 min (A), purity 99%, MS (m/e) 321 MH⁺.

6-(2-(5-Chloro-2-fluorophenyl)pyridin-3-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 971). LCMS: rt 6.20 min (A), purity 99%, MS (m/e) 339 MH⁺.

6-(2-(5-Chloro-2,4-difluorophenyl)pyridin-3-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine(Compound 972). LCMS: rt 6.50 min (A), purity 99%, MS (m/e) 357 MH⁺.

4-(6-Methyl-[2,3′-bipyridin]-2′-yl)quinoline (Compound 973). LCMS: rt2.80 min (B), purity 99%, MS (m/e) 298 (MH⁺).

6-(2-(3-Chloro-2,4-difluorophenyl)pyridin-3-yl)benzo[d]thiazole)(Compound 974). LCMS: rt6.11 min (B), purity 99%, MS (m/e) 359 MH⁺.

Example 82

The following additional 2-chloro-3-(hetero)arylpyridine compounds wereprepared substantially as described herein.

2-Chloro-3,4′-bipyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.68 (d, J=5.7 Hz, 2H), 8.49 (dd, J=4.8,1.9 Hz, 1H), 7.94 (dd, J=7.6, 1.9 Hz, 1H), 7.56 (dd, J=7.6, 4.8 Hz, 1H),7.52 (d, J=5.7 Hz, 2H).

4-(2-Chloropyridin-3-yl)quinoline

¹H NMR (300 MHz, DMSO-d₆): δ 9.01 (d, J=4.4 Hz, 1H), 8.60 (dd, J=4.8,1.9 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.98 (dd, J=7.5, 1.9 Hz, 1H), 7.81(ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.64 (dd, J=7.5, 4.8 Hz, 1H), 7.58 (dd,J=6.9, 1.3 Hz, 1H), 7.51 (d, J=4.4 Hz, 1H), 7.42 (dd, J=8.1, 1.1 Hz,1H).

2′-Chloro-6-methyl-2,3′-bipyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.46 (dd, J=4.8, 2.0 Hz, 1H), 7.99 (dd,J=7.6, 1.9 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.58-7.47 (m, 2H), 7.31 (d,J=7.9 Hz, 1H), 2.52 (s, 3H).

2-(2-Chloropyridin-3-yl)-1,6-naphthyridine

¹H NMR (300 MHz, DMSO-d₆): δ 9.48 (d, J=0.9 Hz, 1H), 8.79 (d, J=6.0 Hz,1H), 8.71 (dd, J=8.6, 0.8 Hz, 1H), 8.57 (ddd, J=4.8, 2.0, 0.7 Hz, 1H),8.16 (ddd, J=7.6, 1.9, 0.7 Hz, 1H), 8.03 (dd, J=8.5, 0.6 Hz, 1H), 7.96(d, J=5.9 Hz, 1H), 7.63 (ddd, J=7.6, 4.8, 0.7 Hz, 1H).

2′-Chloro-[3,3′-bipyridin]-6-amine

¹H NMR (300 MHz, DMSO-d₆): δ 8.34 (dd, J=4.8, 1.7 Hz, 1H), 7.99 (d,J=2.6 Hz, 1H), 7.83 (dd, J=7.6, 1.8 Hz, 1H), 7.52 (dd, J=8.6, 2.5 Hz,1H), 7.46 (dd, J=7.6, 4.7 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 6.20 (s, 2H).

6-(2-Chloropyridin-3-yl)-3-methylimidazo[1,2-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.47 (dd, J=5.2, 1.9 Hz, 1H), 8.40 (s, 1H),8.07-7.97 (m, 1H), 7.61 (d, J=9.3 Hz, 1H), 7.56 (dd, J=7.8, 4.6 Hz, 1H),7.42 (s, 1H), 7.33 (dd, J=9.3, 1.6 Hz, 1H), 2.46 (s, 3H).

6-(2-Chloropyridin-3-yl)-2-methylimidazo[1,2-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.63 (dd, J=1.9, 1.0 Hz, 1H), 8.46 (dd,J=4.8, 1.9 Hz, 1H), 7.97 (dd, J=7.6, 1.9 Hz, 1H), 7.71 (s, 1H),7.59-7.44 (m, 2H), 7.27 (dd, J=9.3, 1.8 Hz, 1H), 2.34 (s, 3H).

2-(2-Chloropyridin-3-yl)-1,5-naphthyridine

¹H NMR (300 MHz, DMSO-d₆): δ 9.06 (dd, J=4.2, 1.7 Hz, 1H), 8.60-8.52 (m,2H), 8.49 (dd, J=8.6, 0.9 Hz, 1H), 8.17 (dd, J=7.6, 2.0 Hz, 1H), 8.12(dd, J=8.7, 0.6 Hz, 1H), 7.85 (dd, J=8.5, 4.2 Hz, 1H), 7.63 (dd, J=7.6,4.8 Hz, 1H).

6-(2-Chloropyridin-3-yl)quinoxaline

¹H NMR (300 MHz, DMSO-d₆): δ 9.01 (s, 2H), 8.51 (dd, J=4.7, 1.9 Hz, 1H),8.25-8.14 (m, 2H), 8.07 (dd, J=7.6, 1.9 Hz, 1H), 7.99 (dd, J=8.7, 1.9Hz, 1H), 7.59 (dd, J=7.5, 4.8 Hz, 1H).

4-(6-(2-Chloropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)morpholine

¹H NMR (300 MHz, DMSO-d₆): δ 8.47 (dd, J=4.8, 1.9 Hz, 1H), 8.28 (dd,J=1.8, 1.0 Hz, 1H), 8.02 (dd, J=7.5, 1.9 Hz, 1H), 7.61-7.51 (m, 2H),7.35 (s, 1H), 7.27 (dd, J=9.3, 1.8 Hz, 1H), 3.97-3.47 (m, 4H), 3.13-2.71(m, 4H).

4-(6-(2-Chloropyridin-3-yl)quinolin-4-yl)morpholine

¹H NMR (300 MHz, DMSO-d₆): δ 8.75 (d, J=5.0 Hz, 1H), 8.47 (dd, J=4.7,1.9 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 8.07-7.95 (m, 2H), 7.79 (dd, J=8.7,2.0 Hz, 1H), 7.57 (dd, J=7.6, 4.8 Hz, 1H), 7.05 (d, J=5.0 Hz, 1H),3.85-3.82 (m, 4H), 3.25-3.12 (m, 4H).

6-(2-Chloropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

¹H NMR (300 MHz, DMSO-d₆): δ 9.70 (d, J=2.4 Hz, 1H), 9.07 (dd, J=2.4 Hz,1H), 8.77 (s, 1H), 8.55 (dd, J=4.8, 2.0 Hz, 1H), 8.12 (dd, J=7.6, 1.9Hz, 1H), 7.63 (dd, J=7.6, 4.8 Hz, 1H).

6-(2-Chloropyridin-3-yl)-N,N-dimethylimidazo[1,2-a]pyridin-3-amine

¹H NMR (300 MHz, DMSO-d₆): δ 8.46 (dd, J=4.7, 1.9 Hz, 1H), 8.19 (dd,J=1.8, 1.0 Hz, 1H), 8.03 (dd, J=7.5, 1.9 Hz, 1H), 7.60-7.49 (m, 2H),7.29 (s, 1H), 7.26 (dd, J=9.4, 1.8 Hz, 1H), 2.75 (s, 6H).

5-(2-Chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidine

¹H NMR (300 MHz, DMSO-d₆): δ 9.24 (dd, J=7.3, 0.9 Hz, 1H), 8.55 (dd,J=4.8, 2.0 Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.14 (dd, J=7.6, 2.0 Hz,1H), 7.61 (dd, J=7.6, 4.8 Hz, 1H), 7.37 (d, J=7.3 Hz, 1H), 6.82 (d,J=2.4 Hz, 1H).

6-(2-Chloropyridin-3-yl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.65 (s, 1H), 8.50 (dd, J=4.8, 1.9 Hz, 1H),8.26 (s, 1H), 8.04 (dd, J=7.6, 1.9 Hz, 1H), 7.91 (d, J=9.6 Hz, 1H), 7.67(d, J=9.4 Hz, 1H), 7.57 (dd, J=7.6, 4.8 Hz, 1H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −59.81 (s).

6-(2-Chloropyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile

¹H NMR (300 MHz, DMSO-d₆): δ 8.82 (d, J=1.9 Hz), 8.54-8.45 (m, 2H), 8.07(dd, J=7.6, 1.9 Hz, 1H), 7.94 (d, J=9.3 Hz, 1H), 7.75 (dd, J=9.3, 1.7Hz, 1H), 7.58 (dd, J=7.6, 4.8 Hz, 1H).

6-(2-Chloropyridin-3-yl)imidazo[1,2-a]pyrimidine

¹H NMR (300 MHz, DMSO-d₆): δ 9.20 (dd, J=2.5, 0.8 Hz, 1H), 8.66 (d,J=2.5 Hz, 1H), 8.51 (dd, J=4.8, 1.9 Hz, 1H), 8.08 (dd, J=7.5, 1.9 Hz,1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.60 (dd, J=7.6, 4.8 Hz, 1H).

6-(2-Chloropyridin-3-yl)-3-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.46 (dd, J=4.8, 1.9 Hz, 1H), 8.25 (d,J=1.7 Hz, 1H), 8.01 (dd, J=7.6, 1.9 Hz, 1H), 7.54 (dd, J=5.1, 2.5 Hz,1H), 7.51 (d, J=0.6 Hz, 1H), 7.25 (s, 1H), 7.21 (dd, J=9.3, 1.8 Hz, 1H),3.16 (t, J=4.3 Hz, 4H), 2.00-1.82 (m, 4H).

(6-(2-Chloropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methanol

¹H NMR (300 MHz, DMSO-d₆): δ 8.51 (d, J=1.7 Hz, 1H), 8.48 (dd, J=4.8,1.9 Hz, 1H), 8.01 (dd, J=7.6, 1.9 Hz, 1H), 7.66 (d, J=9.3 Hz, 1H),7.61-7.53 (m, 2H), 7.40 (dd, J=9.4, 1.8 Hz, 1H), 5.24 (t, J=5.5 Hz, 1H),4.82 (d, J=5.5 Hz, 2H).

4-(6-(2-Chloropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine

¹H NMR (300 MHz, DMSO-d₆): δ 8.65 (d, J=1.7 Hz, 1H), 8.48 (dd, J=4.8,1.9 Hz, 1H), 8.00 (dd, J=7.6, 1.9 Hz, 1H), 7.65 (d, J=9.3 Hz, 1H),7.62-7.54 (m, 2H), 7.37 (dd, J=9.3, 1.8 Hz, 1H), 3.84 (s, 2H), 3.59-3.32(m, 4H), 2.41-2.29 (m, 4H).

6-(2-Chloropyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-carboxamide

¹H NMR (300 MHz, DMSO-d₆): δ 10.17 (s, 1H), 9.55 (dd, J=1.9, 1.0 Hz,1H), 8.63 (s, 1H), 8.51 (dd, J=4.8, 1.9 Hz, 1H), 8.06 (dd, J=7.6, 1.9Hz, 1H), 7.87 (dd, J=9.3, 1.0 Hz, 1H), 7.65 (dd, J=9.3, 1.8 Hz, 1H),7.59 (dd, J=7.6, 4.8 Hz, 1H), 7.16 (s, 2H), 3.76 (s, 6H), 3.63 (s, 3H).

6-(2-Chloropyridin-3-yl)-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.68 (d, J=1.6 Hz, 1H), 8.44 (dd, J=4.8,1.9 Hz, 1H), 8.04 (dd, J=7.6, 1.9 Hz, 1H), 7.81 (d, J=0.8 Hz, 1H), 7.74(d, J=9.3 Hz, 1H), 7.59-7.45 (m, 1H), 7.41 (dd, J=9.3, 1.7 Hz, 1H), 6.95(s, 2H), 3.83 (s, 6H), 3.70 (s, 3H).

1-(6-(2-Chloropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one

¹H NMR (300 MHz, DMSO-d₆): δ 9.61 (d, J=1.8 Hz, 1H), 8.69 (s, 1H), 8.51(dd, J=4.7, 1.9 Hz, 1H), 8.04 (dd, J=7.6, 1.9 Hz, 1H), 7.94 (d, J=9.2Hz, 1H), 7.77 (dd, J=9.2, 1.9 Hz, 1H), 7.59 (dd, J=7.6, 4.7 Hz, 1H),2.58 (s, 3H).

7-(2-Chloropyridin-3-yl)imidazo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.50-8.33 (m, 2H), 7.95 (d, J=6.9 Hz, 1H),7.67 (s, 1H), 7.52 (dd, J=7.6, 4.7 Hz, 1H), 7.45 (s, 1H), 6.78 (d, J=7.3Hz, 1H).

Ethyl 5-(2-chloropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

¹H NMR (300 MHz, DMSO-d₆): δ 8.98 (dd, J=7.2, 0.9 Hz, 1H), 8.59-8.32 (m,2H), 8.12 (dd, J=2.1, 1.0 Hz, 1H), 8.05 (dd, J=7.6, 1.8 Hz, 1H), 7.59(dd, J=7.6, 4.8 Hz, 1H), 7.29 (dd, J=7.1, 2.0 Hz, 1H), 4.29 (q, J=7.1Hz, 2H), 1.30 (t, J=7.0 Hz, 3H).

Methyl 6-(2-chloropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (300 MHz, DMSO-d₆): δ 9.30 (d, J=1.6 Hz, 1H), 8.52 (dd, J=4.8,1.9 Hz, 1H), 8.38 (s, 1H), 8.05 (dd, J=7.6, 1.9 Hz, 1H), 7.93 (d, J=9.4Hz, 1H), 7.72 (dd, J=9.2, 1.6 Hz, 1H), 7.59 (dd, J=7.4, 4.7 Hz, 1H),3.88 (s, 3H).

6-(2-Chloropyridin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide

¹H NMR (300 MHz, DMSO-d₆): δ 9.55 (dd, J=1.9, 0.9 Hz, 1H), 8.54 (t,J=5.7 Hz, 1H), 8.50 (dd, J=4.8, 1.9 Hz, 1H), 8.36 (s, 1H), 8.03 (dd,J=7.6, 1.9 Hz, 1H), 7.81 (d, J=9.4 Hz, 1H), 7.58 (dd, J=9.4, 2.0 Hz,2H), 3.33 (t, J=6.9 Hz, 2H), 3.23 (t, J=7.0 Hz, 4H), 2.19 (t, J=8.0 Hz,2H), 1.91 (dq, J=15.0, 7.5 Hz, 2H), 1.71 (p, J=7.2 Hz, 2H).

7-(2-Chloropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 9.06 (d, J=6.5 Hz, 1H), 8.58 (s, 1H), 8.51(dd, J=4.8, 1.9 Hz, 1H), 8.03 (dd, J=7.6, 1.9 Hz, 1H), 7.99 (s, 1H),7.58 (dd, J=7.6, 4.8 Hz, 1H), 7.34 (dd, J=7.1, 1.8 Hz, 1H).

6-(2-Chloropyridin-3-yl)pyrido[2,3-b]pyrazine

¹H NMR (300 MHz, DMSO-d₆): δ 9.20 (d, J=1.6 Hz, 1H), 9.12 (d, J=1.6 Hz,1H), 8.70 (d, J=8.6 Hz, 1H), 8.59 (dd, J=4.8, 1.9 Hz, 1H), 8.25 (d,J=8.6 Hz, 1H), 8.21 (dd, J=7.6, 1.9 Hz, 1H), 7.65 (dd, J=7.6, 4.8 Hz,1H).

5-(2-Chloropyridin-3-yl)pyrazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.76 (dd, J=7.2, 0.9 Hz, 1H), 8.47 (dd,J=4.8, 1.9 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H), 7.99 (dd, J=7.6, 1.9 Hz,1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H), 7.55 (dd, J=7.6, 4.8 Hz, 1H), 6.99(dd, J=7.2, 2.0 Hz, 1H), 6.70 (dd, J=2.2, 0.9 Hz, 1H).

4-(2-Chloropyridin-3-yl)-2-fluorobenzonitrile

¹H NMR (300 MHz, DMSO-d₆): δ 8.50 (dd, J=4.8, 1.9 Hz, 1H), 8.05 (dd,J=8.0, 7.0 Hz, 1H), 7.95 (dd, J=7.6, 1.9 Hz, 1H), 7.76 (dd, J=10.4, 1.5Hz, 1H), 7.62-7.51 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ −108.27 (dd,J=10.5, 7.0 Hz).

5-(2-Chloropyridin-3-yl)-2-fluorobenzonitrile

¹H NMR (300 MHz, DMSO-d₆): δ 8.47 (dd, J=4.8, 1.9 Hz, 1H), 8.11 (dd,J=6.2, 2.2 Hz, 1H), 7.97-7.94 (m, 1H), 7.94-7.90 (m, 1H), 7.65 (t, J=9.1Hz, 1H), 7.55 (dd, J=7.6, 4.8 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−109.00 (dt, J=9.4, 5.7 Hz).

6-(2-Chloropyridin-3-yl)pyrido[2,3-d]pyrimidin-4-amine

¹H NMR (300 MHz, DMSO-d₆): δ 9.09 (d, J=2.4 Hz, 1H), 8.83 (d, J=2.4 Hz,1H), 8.56 (s, 1H), 8.52 (dd, J=4.8, 1.9 Hz, 1H), 8.17 (br s, 2H), 8.07(dd, J=7.6, 1.9 Hz, 1H), 7.62 (dd, J=7.6, 4.8 Hz, 1H).

6-(2-Chloropyridin-3-yl)-7-methylimidazo[1,2-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.50 (dd, J=4.8, 2.0 Hz, 1H), 8.49 (s, 1H),7.93 (dd, J=7.5, 2.0 Hz, 1H), 7.85 (d, J=0.9 Hz, 1H), 7.58-7.53 (m, 2H),7.52 (app s 1H), 2.06 (d, J=0.9 Hz, 3H).

6-(2-Chloropyridin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.59 (s, 1H), 8.53 (dd, J=4.8, 1.9 Hz, 1H),7.99 (dd, J=7.6, 1.9 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.62-7.56 (m, 2H),2.53 (s, 3H).

6-(2-Chloropyridin-3-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.53 (dd, J=4.8, 1.9 Hz, 1H),8.48 (s, 1H), 7.97 (dd, J=7.5, 1.9 Hz, 1H), 7.83 (s, 1H), 7.58 (dd,J=7.5, 4.8 Hz, 1H), 2.15 (s, 3H).

6-(2-Chloropyridin-3-yl)imidazo[1,2-b]pyridazine

¹H NMR (300 MHz, DMSO-d₆): δ 8.58 (dd, J=4.8, 1.9 Hz, 1H), 8.38 (d,J=0.8 Hz, 1H), 8.25 (d, J=9.4 Hz, 1H), 8.13 (dd, J=7.6, 1.9 Hz, 1H),7.87 (d, J=0.8 Hz, 1H), 7.62 (dd, J=7.6, 4.8 Hz, 1H), 7.50 (d, J=9.4 Hz,1H).

6-(2-Chloropyridin-3-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 9.14 (d, J=1.4 Hz, 1H), 8.67 (s, 1H), 8.51(dd, J=4.8, 1.9 Hz, 1H), 8.05 (dd, J=7.6, 1.9 Hz, 1H), 7.90 (dd, J=11.1,1.4 Hz, 1H), 7.58 (dd, J=7.6, 4.8 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆): δ−129.92 (d, J=11.2 Hz).

7-Chloro-6-(2-chloropyridin-3-yl)imidazo[1,2-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.53 (dd, J=4.8, 1.9 Hz, 1H),8.03-7.95 (m, 2H), 7.67 (d, J=1.2 Hz, 1H), 7.58 (dd, J=7.5, 4.8 Hz, 1H).

6-(2-Chloropyridin-3-yl)quinolin-4-amine

¹H NMR (300 MHz, DMSO-d₆): δ 8.46 (d, J=4.3 Hz, 1H), 8.33 (d, J=5.2 Hz,1H), 8.24 (s, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.69(d, J=9.6 Hz, 1H), 7.56 (dd, J=7.4, 4.9 Hz, 1H), 6.85 (br s, 2H), 6.56(d, J=5.0 Hz, 1H).

6-(2-Chloropyridin-3-yl)-4-methoxyquinoline

¹H NMR (300 MHz, DMSO-d₆): δ 8.79 (d, J=5.3 Hz, 1H), 8.47 (dd, J=4.8,1.7 Hz, 1H), 8.17 (d, J=2.1 Hz, 1H), 8.06-7.94 (m, 2H), 7.83 (dd, J=8.7,2.1 Hz, 1H), 7.55 (dd, J=7.6, 4.8 Hz, 1H), 7.08 (d, J=5.2 Hz, 1H), 4.04(s, 3H).

6-(2-Chloropyridin-3-yl)quinoline-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆): δ 9.02 (d, J=4.3 Hz, 1H), 8.49 (dd, J=4.7,1.8 Hz, 1H), 8.29 (d, J=1.8 Hz, 2H), 8.16 (d, J=8.7 Hz, 1H), 8.00 (dd,J=7.5, 1.8 Hz, 1H), 7.92 (dd, J=8.7, 2.0 Hz, 2H), 7.63 (d, J=4.3 Hz,1H), 7.58 (dd, J=7.6, 4.8 Hz, 1H).

6-(2-Chloropyridin-3-yl)imidazo[1,2-b]pyridazine-3-carbonitrile

¹H NMR (300 MHz, DMSO-d₆): δ 8.67 (s, 1H), 8.62 (dd, J=4.8, 1.9 Hz, 1H),8.52 (d, J=9.5 Hz, 1H), 8.17 (dd, J=7.6, 1.9 Hz, 1H), 7.90 (d, J=9.5 Hz,1H), 7.67 (dd, J=7.6, 4.8 Hz, 1H).

6-(2-Chloropyridin-3-yl)-[1,2,4]triazolo[1,5-b]pyridazine

¹H NMR (300 MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.61 (d, J=4.8, 1.9 Hz, 1H),8.59 (d, J=9.4 Hz, 1H), 8.19 (dd, J=7.6, 1.9 Hz, 1H), 8.01 (d, J=9.4 Hz,1H), 7.66 (dd, J=7.6, 4.8 Hz, 1H).

7-(2-Chloro-5-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 9.06 (dd, J=7.1, 0.9 Hz, 1H), 8.58 (s, 1H),8.23 (d, J=3.0 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.67 (d, J=3.0 Hz, 1H),7.36 (dd, J=7.1, 1.9 Hz, 1H), 3.89 (s, 3H).

7-(2-Chloro-5-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 9.09 (dd, J=7.1, 0.9 Hz, 1H), 8.60 (s, 1H),8.59 (d, J=3.0 Hz, 1H), 8.13 (dd, J=8.6, 3.0 Hz, 1H), 8.05 (dd, J=1.8,0.9 Hz, 1H), 7.38 (dd, J=7.1, 1.8 Hz, 2H).

7-(2-Chloro-5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 9.05 (d, J=8.0 Hz, 1H), 8.57 (s, 1H), 8.34(d, J=2.3 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.33(dd, J=7.1, 1.9 Hz, 1H), 2.35 (s, 3H).

7-(2-Chloropyridin-3-yl)-1-methylquinoxalin-2(1H)-one

¹H NMR (300 MHz, DMSO-d₆): δ 8.49 (dd, J=4.8, 1.9 Hz, 1H), 8.27 (s, 1H),8.00 (dd, J=7.6, 1.9 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.68 (d, J=1.7 Hz,1H), 7.58 (dd, J=7.6, 4.8 Hz, 1H), 7.50 (dd, J=8.2, 1.8 Hz, 1H), 3.62(s, 4H).

7-(2-Chloropyridin-3-yl)quinoxalin-2(1H)-one

¹H NMR (300 MHz, DMSO-d₆): δ 12.51 (s, 1H), 8.48 (dd, J=4.7, 1.9 Hz,1H), 8.21 (s, 1H), 7.94 (dd, J=7.6, 1.9 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H),7.56 (dd, J=7.6, 4.7 Hz, 1H), 7.42-7.33 (m, 2H).

7-(2-Chloropyridin-3-yl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

¹H NMR (300 MHz, DMSO-d₆): δ 12.47 (s, 1H), 8.45 (dd, J=4.8, 1.9 Hz,1H), 8.03 (s, 1H), 7.93 (dd, J=7.6, 1.9 Hz, 1H), 7.88 (d, J=1.9 Hz, 1H),7.80 (dd, J=8.5, 2.0 Hz, 1H), 7.53 (dd, J=7.6, 4.8 Hz, 1H), 7.43 (d,J=8.5 Hz, 1H).

7-(2-Chloropyridin-3-yl)-2-methyl-2H-benzo[e][1,2,4]thiadiazine1,1-dioxide

¹H NMR (300 MHz, DMSO-d₆): δ 8.47 (dd, J=4.8, 1.9 Hz, 1H), 8.12 (s, 1H),7.96-7.94 (m, 2H), 7.90 (d, J=2.1 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.55(dd, J=7.6, 4.8 Hz, 1H), 3.66 (s, 3H).

Ethyl 5-(2-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

¹H NMR (300 MHz, DMSO-d₆): δ 9.40 (d, J=7.3 Hz, 1H), 8.69 (s, 1H),8.64-8.50 (m, 1H), 8.17 (dd, J=7.7, 1.9 Hz, 1H), 7.76-7.58 (m, 2H), 4.27(q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).

5-(2-Chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

¹H NMR (300 MHz, DMSO-d₆): δ 9.50 (dd, J=7.2, 0.9 Hz, 1H), 8.90 (s, 1H),8.60 (dd, J=4.7, 1.9 Hz, 1H), 8.20 (dd, J=7.6, 1.9 Hz, 1H), 7.75 (d,J=7.2 Hz, 1H), 7.65 (dd, J=7.6, 4.8 Hz, 1H).

N-(2′-chloro-[3,3′-bipyridin]-6-yl)acetamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (s, 1H), 8.44 (dd, J=4.7, 1.9 Hz, 1H),8.40 (d, J=2.5 Hz, 1H), 8.16 (d, J=8.7 Hz, 1H), 8.02-7.84 (m, 2H), 7.53(dd, J=7.6, 4.8 Hz, 1H), 2.11 (s, 3H).

5-(2-Chloropyridin-3-yl)thiazolo[5,4-b]pyridin-2-amine

¹H NMR (300 MHz, DMSO-d₆): δ 8.44 (dd, J=4.7, 1.9 Hz, 1H), 8.04 (dd,J=7.6, 1.9 Hz, 1H), 7.94 (s, 2H), 7.70 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.3Hz, 1H), 7.52 (dd, J=7.6, 4.7 Hz, 1H).

5-(2-Chloropyridin-3-yl)thiazolo[5,4-b]pyridine

¹H NMR (300 MHz, DMSO-d₆): δ 9.63 (s, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.53(dd, J=4.7, 1.9 Hz, 1H), 8.12 (dd, J=7.6, 1.9 Hz, 1H), 7.94 (d, J=8.5Hz, 1H), 7.59 (dd, J=7.6, 4.8 Hz, 1H).

Example 83

2-(6-(2-Chloropyridin-3-yl)-1H-indazol-1-yl)acetamide and2-(6-(2-chloropyridin-3-yl)-2H-indazol-2-yl)acetamide can be prepared asshown in Scheme 33, and as described below:

6-(2-Chloropyridin-3-yl)-1H-indazole (0.6 g, 2.6 mmol), 2-bromoacetamide(0.5 g, 3.4 mmol) and Cs₂CO₃ (1.3 g, 3.9 mmol) in dry DMF (2.5 mL) wasstirred under argon in a screw capped vial at room temperature. Thereaction mixture was diluted with water after 2 days and the resultantsolid was collected by filtration. Individual alkylated indazoleregio-isomers were isolated by from the solid by purification(Combiflash® Companion System® with RediSep® silica gel column 24 g and30-50-75% EtOAC/hexanes as an eluting solvent).2-(6-(2-chloropyridin-3-yl)-1H-indazol-1-yl)acetamide (fast elutedN1-regio-isomer): ¹H NMR (300 MHz, DMSO-d₆): δ 8.45 (dd, J=4.7, 1.9 Hz,1H), 8.12 (s, 1H), 7.91 (dd, J=7.6, 1.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H),7.71 (s, 1H), 7.54 (dd, J=7.6, 4.7 Hz, 2H), 7.23 (dd, J=8.3, 1.4 Hz,2H), 5.08 (s, 2H). 2-(6-(2-Chloropyridin-3-yl)-2H-indazol-2-yl)acetamide(late eluted N2-regio-isomer: ¹H NMR (300 MHz, DMSO-d₆): δ 8.43 (dd,J=4.7, 1.9 Hz, 1H), 8.40 (d, J=0.8 Hz, 1H), 7.91 (dd, J=7.5, 1.9 Hz,1H), 7.80 (dd, J=8.6, 0.8 Hz, 1H), 7.74-7.61 (m, 2H), 7.52 (dd, J=7.6,4.8 Hz, 1H), 7.35 (s, 1H), 7.10 (dd, J=8.6, 1.4 Hz, 1H), 5.12 (s, 2H).

Example 84

6-Bromo-3-methylimidazo[1,2-a]pyridine can be prepared as shown inScheme 34, and as described below:

2-Bromo-1,1-diethoxypropane (5 g) was added to a stirring solution ofaq. 1N HCl (15 mL) and heated at 90° C. for 1 h. The clear reactionmixture was cooled to room temperature and treated with solid NaHCO₃till pH 7.0. 2-amino-5-bromopyridine (1.8 G) and MeOH (25 mL) weretransferred successively to the above reaction mixture and heated at 90°C. After 8h, the reaction mixture was concentrated under vacuum byrotary evaporator. The resulting solid concentrate was stirred inCH₂Cl₂/water (200 mL/75 ml). Organic layer was separated, dried overMgSO₄, filtered and concentrated. The crude concentrate was stirred inEtOAc (30 mL) and the solid was collected by filtration to obtain6-bromo-3-methylimidazo[1,2-a]pyridine as a tan solid (1.6 g). ¹H NMR(300 MHz, DMSO-d₆): δ 8.55 (s, 1H), 7.50 (d, J=9.5 Hz, 1H), 7.37 (s,1H), 7.28 (d, J=9.5 Hz, 1H), 2.44 (s, 3H).

Example 85

6-Iodo-2-methylimidazo[1,2-a]pyridine can be prepared as shown in Scheme35, and as described below:

Chloroacetone (3 mL) was added to a stirring solution of2-amino-5-iodopyridine (2 g) in EtOH (20 mL) and heated to reflux. Thereaction progress (50% of unreacted 2-amino-5-iodopyridine) was analyzedafter 12h by LC/MS and TLC. Additional amount of chloroacetone (3 mL)was transferred to the reaction mixture and heated for additional 8h toobserve the >90% consumption of 2-amino-5-iodopyridine. The reactionmixture was cooled and concentrated to dryness. The crude residue wasdiluted with EtOAc (130 mL)/water (50 mL) and neutralized with 5% aq.NaOH (25 mL). Organic layer from the biphasic solution was separated andthe aqueous phase was partitioned again with EtOAc (70 mL). Combinedorganic layers were dried over MgSO₄, filtered and concentrated. Thecrude brown residue was purified by Combiflash® companion System® withRediSep® silica gel column [(80 g), 50-75-100% EtOAC/hexanes as aneluting solvent gradient. The product fractions were concentrated toprovide 2.2 g of 6-iodo-2-methylimidazo[1,2-a]pyridine (1.8 g) as anoff-brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.81 (dd, J=1.7, 1.0 Hz,1H), 7.62-7.55 (app s, 1H), 7.31 (dd, J=9.4, 1.7 Hz, 1H), 7.25 (dd,J=9.3, 0.8 Hz, 1H), 2.29 (s, 3H). See Helvetica Chimica Acta, 90(12),2349-2367 (2007).

Example 86 6-Iodo-2-methylimidazo[1,2-a]pyridine

6-Iodo-2-methylimidazo[1,2-a]pyridine can be prepared via the proceduresdescribed in J. Med. Chem, 54(7), 2455-66 (2011). ¹H NMR (300 MHz,DMSO-d₆) δ 8.38 (dd, J=1.9, 0.9 Hz, 1H), 7.47 (dd, J=9.5, 0.8 Hz, 1H),7.33 (s, 1H), 7.26 (dd, J=9.5, 2.0 Hz, 1H), 3.78-3.75 (m 4H), 3.07-2.80(m, 5H).

Example 87

4-(6-Bromoquinolin-4-yl)morpholine can be prepared as shown in Scheme36, and as described below:

6-Bromo-4-chloroquinoline (1.0 G, 4.1 mmol), morpholine (0.468 g, 5.3mmol) and K₂CO₃ (1.0 G, 7.2 mmol) in NMP (5 mL) were heated at 100° C.for 12h. The reaction mixture was cooled to room temperature, dilutedwith water (20 mL) and the product was extracted into EtOAc/hexanes (140mL/60 mL). The organic layer was washed with water (75 mL) and brine (20mL) successively, dried over MgSO₄ and filtered. The filtrate wasconcentrated and purified by flash column chromatography (Combiflash®Companion System® with RediSep® silica gel column 40 g and 30-70%EtOAC/hexanes as an eluting solvent]. The product fractions wereconcentrated to provide 4-(6-bromoquinolin-4-yl)morpholine (700 mg) as awhite solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (d, J=5.0 Hz, 1H), 8.13(d, J=2.2 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.81 (dd, J=9.0, 2.2 Hz, 1H),7.06 (d, J=5.0 Hz, 1H), 3.87-3.84 (m, 4H), 3.18-3.02 (m, 4H).

Example 88

6-Bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine can be prepared asshown in Scheme 37, and as described below:

A screw capped vial (20 mL) containing a stir bar was charged with6-bromo-3-iodoimidazo[1,2-a]pyridine (0.27 g) followed by dry DMF (4 mL)and (Phen)CuCF₃ sequentially. The capped vial containing initial darkreaction mixture was stirred at 50° C. The reaction mixture changedcolors as it progressed from pink to off-yellow and off-green at the endof the reaction. The progress was monitored intermittently by LC/MS.After 48h, the reaction mixture was diluted with EtOAc/CH₂Cl₂ (1:1, 50mL) and filtered through a pad of Celite®/Fluorosil® and washed the padwith additional amount of EtOAc/CH₂Cl₂ (1:1, 50 mL). The filtrate wasconcentrated by rotary evaporator under vacuum to dryness. The crudeconcentrate was diluted with water, sonicated for 10 min and filtered.The collected solid was suction dried to provide the desired6-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine along with3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyridine (12:1) which can beused in the subsequent coupling with no further purification. SeeHartwig Angew. Int. Ed. Eng. 2011, 50, 3793-3794.

Example 89

6-Bromoimidazo[1,2-a]pyridine-3-carbonitrile can be prepared as shown inScheme 38:

See J. Med. Chem., 54(7), 2455-66 (2011).

Example 90 4-(6-Bromoimidazo[1,2-a]pyridin-3-yl)morpholine

4-(6-Bromoimidazo[1,2-a]pyridin-3-yl)morpholine can be prepared asdescribed in J. Med. Chem., 54(7), 2455-66 (2011). ¹H NMR (300 MHz,DMSO-d₆) δ 8.38 (dd, J=1.9, 0.9 Hz, 1H), 7.47 (dd, J=9.5, 0.8 Hz, 1H),7.33 (s, 1H), 7.26 (dd, J=9.5, 2.0 Hz, 1H), 3.78-3.75 (m 4H), 3.07-2.80(m, 5H).

Example 91 4-(6-Bromo-3-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine

4-(6-Bromo-3-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine can be prepared asdescribed in J. Med. Chem., 54(7), 2455-66 (2011).

Example 92

6-Bromoimidazo[1,2-a]pyridine-3-carbonitrile can be prepared as shown inScheme 39:

Stirring solution of 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde [seeBioorg. Med. Chem. Let. 15(17), 5837-5844; 2007; Int'l Pat. App. Pub.no, 2011/055320] (1.5g, 6.6 mmol) in MeOH (20 mL) was cooled to 0° C.and NaBH₄ (0.50 g, 13.2 mmol) was added in portions for a period of 20min. Cooling was removed after 1 h and allowed to stir for 3h. Thereaction mixture was quenched with water and concentrated by rotaryevaporator to dryness. Subsequently, the solid concentrate was dilutedwith water and collected on the Buchner funnel by suction filtration.The solid was suction dried to obtain(6-bromoimidazo[1,2-a]pyridin-3-yl)methanol as a pale yellow crystallinesolid (0.83 g). ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (dd, J=2.0, 0.9 Hz,1H), 7.55 (dd, J=9.5, 0.9 Hz, 1H), 7.52 (s, 1H), 7.36 (dd, J=9.5, 2.0Hz, 1H), 5.27 (t, J=5.4 Hz, 1H), 4.79 (d, J=5.3 Hz, 2H). See J. Med.Chem., 54(7), 2455-66 (2011).

Example 93

4-((6-Bromoimidazo[1,2-a]pyridin-3-yl)methyl)morpholine can be preparedas shown in Scheme 40:

Morpholine (1.91 g, 22 mmol) and 37% aq. formaldehyde (5 mL, 60 mmol) inacetonitrile:water (6:1, mL) was stirred for 15 min at room temperature.6-bromoimidazo[1,2-a]pyridine (3.94 g, 20 mmol) and Sc(OTf)₃ were addedsequentially to the above solution and stirred for 36h at roomtemperature to observe the complete consumption of6-bromoimidazo[1,2-a]pyridine. The reaction mixture was concentrated,diluted with aq.K₂CO₃ (150 mL) and stirred the suspension for 25 min.The solid was collected by filtration and dried on the funnel to obtain44-(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (3.9 g). ¹H NMR(300 MHz, DMSO-d₆) δ 8.69 (d, J=1.7 Hz, 1H), 7.54 (d, J=9.6 Hz, 1H),7.51 (s, 1H), 7.34 (dd, J=9.5, 1.7 Hz, 1H), 3.81 (s, 2H), 3.64-3.39 (m,3H), 2.43-2.26 (m, 3H). See U.S. Pat. App. Pub. no. 2005/0054701.

Example 94

46-Bromo-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-carboxamidecan be prepared as shown in Scheme 41:

A stirring solution of 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid(0.91 g, 3.7 mmol), EDCI (1.08 g, 5.6 mmol), HOBt (0.76 g, 5.6 mmol) and3,4,5-trimethoxyaniline (0.76 g, 4.1 mmol) in acetonitrile/DMF (8/3 mL)under argon was added i-Pr₂NEt (2.00 g, 2.6 ml), 15.4 mmol) drop wisefor 5 min at room temperature. The resulting off-brown homogeneousreaction mixture was continued to stir at room temperature for 18h.Subsequently, the heterogeneous reaction mixture was diluted with waterand the solid was collected by filtration. The solid was suction driedon funnel to obtain6-bromo-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-carboxamide(1.1 g) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.17 (s, 1H),9.64 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 7.75 (d, J=9.7 Hz, 1H), 7.64 (dd,J=9.5, 1.9 Hz, 1H), 7.15 (s, 2H), 3.78 (s, 6H), 3.63 (s, 3H).

Similarly, the following compounds can be prepared:

6-Bromo-N-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

6-Bromo-N-(3-(2-oxopyrrolidin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide

Example 95

6-Bromoimidazo[1,2-a]pyridine-3-carboxylic acid can be prepared as shownin Scheme 42 or Scheme 43:

A stirring solution of 6-bromoimidazo[1,2-a]pyridine-3-carbonitrile [JMC54(7). 2455-2466; 2011] (1.0 g), EtOH (10 mL) and aq. NaOH (1.0 g, 10mL) was heated at 100° C. After 12h, the reaction mixture was cooled andconcentrated to dryness by rotary evaporator under reduced pressure.Subsequently, the crude solid was diluted with water, cooled in ice-bathand acidified with conc. HCl till pH 4 while stirring. The resultingsuspension was suction filtered and the solid was dried overnight.Subsequently, the collected solid was further dried over P₂O₅ under highvacuum to obtain 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (0.91g) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.27 (s, 1H), 9.36 (s,1H), 8.24 (s, 1H), 7.77 (d, J=9.5 Hz, 1H), 7.67 (d, J=9.5, 1.7 Hz, 1H).

Reaction mixture containingN′-(5-bromopyridin-2-yl)-N,N-dimethylformimidamide (6.5 g, 28.5 mmol),methyl 2-bromoacetate (5.6 g, 3.5 mL, 37.0 mmol) and NaHCO₃ (4.1 g, 48.8mmol) in i-PrOH (60 mL) was heated at 90° C. under nitrogen. The heatingwas stopped after 12h and cooled the dense heterogeneous reactionmixture to room temperature. The reaction mixture was concentrated anddiluted with water. The resultant slurry was collected by suctionfiltration and obtained methyl6-bromoimidazo[1,2-a]pyridine-3-carboxylate (6.9 g) as a tan white solidupon drying. ¹H NMR (300 MHz, DMSO-d₆): δ 9.31 (d, J=1.8 Hz, 1H), 8.31(s, 1H), 7.80 (d, J=9.5 Hz, 1H), 7.71 (dd, J=9.5, 1.6 Hz, 1H), 3.88 (s,4H). Ester hydrolysis was done by stirring a solution of methyl6-bromoimidazo[1,2-a]pyridine-3-carboxylate (2.5 g), LiOH.H₂O (1.2 g) inTHF/MeOH/H₂O (1/1/1, 75 mL) at room temperature. Reaction mixture wasconcentrated upon complete hydrolysis of ester to corresponding acid,diluted with water/ice and acidified with 2N. aq HCl until pH 6. Theresulting solid was filtered, suction dried followed by drying underP₂O₅ under vacuum to obtain 6-bromoimidazo[1,2-a]pyridine-3-carboxylicacid (2.2 g) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.27 (s,1H), 9.36 (s, 1H), 8.24 (s, 1H), 7.77 (d, J=9.5 Hz, 1H), 7.67 (d, J=9.5,1.7 Hz, 1H).

Example 96

6-Bromo-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine can be preparedas shown in Scheme 44:

A reaction flask was charged with 6-bromo-3-iodoimidazo[1,2-a]pyridine(2.0 g, 6.2 mmol), (3,4,5-trimethoxyphenyl)boronic acid (1.44 g, 6.8mmol), 2M. aq. Na₂CO₃ (8 mL, 16 mmol), 1,4-dioxane (50 mL) and a stirbar. The contents were degassed by vacuum and back filled with argon inthree times while stirring. Subsequently, catalyst Pd(PPh₃)₄ (0.35 g,0.30 mmol) was added to the reaction contents, repeated degassing cyclesand heated at 90° C. for 12h. Reaction mixture was cooled and filteredthe biphasic reaction mixture through Celite® and concentrated thefiltrate. The crude solid residue was partitioned between CH₂Cl₂ (150mL)/water (50 mL). The organic layer was separated, dried over MgSO₄,filtered and concentrated. The crude concentrate (2.2 g) was subjectedto purification by flash column chromatography (Combiflash® companionSystem® with RediSep® silica gel column 40 g, 30-60% EtOAC/hexanes as aneluting solvent) to obtain6-bromo-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine as a whitesolid (1.0 g).

Example 97

1-(6-Bromoimidazo[1,2-a]pyridin-3-yl)ethan-1-one can be prepared asshown in Scheme 45:

(E)-N′-(5-Bromopyridin-2-yl)-N,N-dimethylformimidamide (2.0 g, 8.8mmol), 1-chloropropan-2-one (1.2 mL, 1.4 g, 15 mmol), NaHCO₃ (1.3 g,15.5 mmol) in 2-propanol (30 mL) were heated at 90° C. under nitrogenfor 12h. The dark reaction mixture was cooled and the denseheterogeneous suspension was diluted with water. The solid was collectedby filtration, washed with water and dried to obtain 1.0 g of1-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethan-1-one. ¹H NMR (300 MHz,DMSO-d₆) δ 9.62 (d, J=1.9 Hz, 1H), 8.61 (s, 1H), 7.81 (d, J=9.5 Hz, 1H),7.75 (dd, J=9.5, 1.9 Hz, 1H), 2.55 (s, 3H). See Bioorg. Med. Chem. Lett.15(1), 403412 (2007); Int'l Pat. App. Pub. no. 2009/158011.

Example 98 7-Bromoimidazo[1,5-a]pyridine

7-Bromoimidazo[1,5-a]pyridine can be prepared as described in Int'l Pat.App. Pub. no. 2005090304.

Example 99

1-(6-Bromoimidazo[1,2-a]pyridin-3-yl)ethan-1-one can be prepared asshown in Scheme 46:

A reaction flask was charged with 1-bromo-3-(methyl-d₃)benzene (2.0 g,11.5 mmol), bis(pinacolato)diboron (5.8 g, 23 mmol) and KOAc (2.25 g, 23mmol), DMF (20 mL) and a stir bar. The contents were degassed by vacuumand back filled with argon three times while stirring. Subsequently,catalyst PdCl₂ (dppf).CH₂Cl₂ (0.85 g, 1.15 mmol) was added to thereaction contents, repeated degassing cycles and heated at 100° C. for12h. Reaction mixture was cooled and filtered the reaction mixturethrough Celite®. The filtrate cake was washed with EtOAc (30 mL) and thefiltrate was partitioned between EtOAc (150 mL)/water (40 mL). Organiclayer was separated and the aqueous layer was extracted with additionalEtOAc. Combined organic layers were stirred overMgSO₄/Celite®/Fluorosil® and filtered. The filtrate was concentrated andpurified by flash column chromatography (Combiflash® companion System®with RediSep® silica gel column 80 g, 10-20% EtOAC/hexanes as elutant)to obtain4,4,5,5-tetramethyl-2-(3-(methyl-d₃)phenyl)-1,3,2-dioxaborolaneas a semisolid (2.85 g) and used in the boronate coupling with no furtherpurification.

Example 100

Triazolopyrimidines can be prepared using the protocol of Scheme 47,described as in Huntsman, E and Balsells, J., Eur. J. Org. Chem. 2005,(17), 3761-3765:

The following compounds were made:

6-Bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (s, 1H), 7.83 (d, J=9.4 Hz, 1H), 7.69(d, J=9.4 Hz, 1H), 2.84 (s, 3H).

6-Bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.44 (s, 1H), 7.86 (s, 1H),2.45 (s, 3H).

6-Bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine

¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (app dd, J=1.5, 0.7 Hz, 1H), 8.59 (s,1H), 7.98 (dd, J=9.9, 1.5 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.85(d, J=9.9 Hz).

Example 101

6-Bromoimidazo[1,2-b]pyridazine-3-carbonitrile can be prepared as shownin Scheme 48:

Example 102 (E)-N′-(6-Bromopyridazin-3-yl)-N,N-dimethylformimidamide

3-Amino-6-bromopyridazine (5.0 g, 28.7 mmol) was heated and stirred withdimethylformamide dimethylacetal (5.36 g, 6.0 mL, 45.0 mmol) undernitrogen at 110° C. for 3h. The brown homogeneous reaction mixture wascooled to room temperature. The resulting heterogeneous slurry wasstirred in EtOAc/hexanes (1:1, 75 mL) and filtered. The filtered solidwas suction dried to obtain apparently(E)-N′-(6-bromopyridazin-3-yl)-N,N-dimethylformimidamide (4.9 g) as apale pink crystalline solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (s, 1H),7.64 (d, J=9.1 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 3.11 (s, 3H), 3.00 (s,3H).

Example 103 6-Bromoimidazo[1,2-b]pyridazine-3-carbonitrile

(E)-N′-(6-Bromopyridazin-3-yl)-N,N-dimethylformimidamide (2.5 g, 10.9mmol), bromoacetonitrile (3.92 g, 32.7 mmol) and NaHCO₃ (1.8 g, 21.8mmol) in i-PrOH (15 mL) were heated at 75° C. for 8h while stirring thecontents. Subsequently, the dark reaction mixture was diluted with waterand the resulting solid was collected by filtration. The solid waspurified by flash chromatography (Combiflash® Companion System® withRediSep® silica gel column 40 g and 15-30-50% EtOAC/hexanes as aneluting solvent) to obtain 1.3 g of6-bromoimidazo[1,2-b]pyridazine-3-carbonitrile. ¹H NMR (300 MHz,DMSO-d₆) δ 8.58 (s, 1H), 8.33 (d, J=9.5 Hz, 1H), 7.77 (d, J=9.5 Hz, 1H).

Example 104 6-Chloro-[1,2,4]triazolo[1,5-b]pyridazine

(6-Chloro-[1,2,4]triazolo[1,5-b]pyridazine can be prepared as describedin J. Het. Chem., 12(1), 107-110 (1975).

Example 105

Bromopyrido[2,3-d]pyrimidin-4-amine can prepared as shown in Scheme 49,and as described below:

6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one

2-Amino-5-bromonictoinic acid (2 g) and formamidine acetate (3.0 g) wereheated at 120° C. in 2-methoxyethanol (15 ml) for 36 h under argon. Theheterogeneous reaction mixture was diluted with water and filtered. Thesolid was suction dried to obtain 1.7 g of6-bromopyrido[2,3-d]pyrimidin-4(3H)-one. ¹H NMR (300 MHz, DMSO-d₆) δ12.70 (s, 1H), 9.01 (d, J=2.6 Hz, 1H), 8.59 (d, J=2.6 Hz, 1H), 8.33 (s,1H).

6-Bromo-4-chloropyrido[2,3-d]pyrimidine

6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one (3.0g) and POCl₃ (15 mL) wereheated at 130° C. under nitrogen for 3h. The homogeneous dark solutionwas concentrated under reduced pressure and diluted with EtOAc (150 mL).The heterogeneous brown slurry was poured onto mixture of ice/aq. NaHCO₃and allowed the mixture warm to room temperature. The heterogeneousbrown mixture was further diluted with EtOAc (75 mL) and separated theorganic layer. The organic layer was partitioned with aq. NaCl,separated, stirred with MgSO₄ and filtered through a pad of Celite® andsilica gel. The pale yellow filtrate was concentrated and the crudesolid was stirred in 50% EA/hexanes.6-Bromo-4-chloropyrido[2,3-d]pyrimidine was obtained as a pale yellowcrystalline solid (1.8 g, purity: 95%) upon filtration.

6-Bromopyrido[2,3-d]pyrimidin-4-amine

6-Bromo-4-chloropyrido[2,3-d]pyrimidine (1.0 g) and 4% NH₃ in i-PrOH (25mL) were stirred in a sealed tube at room temperature overnight. Thepale brown heterogeneous slurry was concentrated, diluted with water andfiltered. The brown solid thus collected was suction dried to obtain6-bromopyrido[2,3-d]pyrimidin-4-amine (1.3 g, purity: 97%). ¹H NMR (300MHz, DMSO-d₆) δ 9.09 (d, J=2.5 Hz, 1H), 9.01 (d, J=2.5 Hz, 1H), 8.52 (s,1H), 8.31 (br s, 2H).

Biological Example 1 AlphaScreen® SureFire® SMAD3 (p-Ser423/425) Assay

The p-SMAD-3 (Ser423/425) SureFire® assay has been designed to measurethe phosphorylation of endogenous cellular p-SMAD-3 (Ser423/425) in celllysates and is a system for the screening of both modulators of receptoractivation (e.g. agonists and antagonists) as well as agents actingintracellularly, such as small molecule inhibitors of upstream events.The assay will measure p-SMAD-3 (Ser423/425) activation by either clonedor endogenous receptors, and can be applied to primary cells.

P-SMAD-3 (Ser423/425) SureFire® Assay Protocols

Step A: Preparation of Buffers

1× Lysis buffer: 1 ml of 5× Lysis buffer was diluted with 4 ml ofsterile water. After dilution, excess 1× Lysis buffer can be frozen andthawed up to 5 times without loss in activity.

Activation buffer: The buffer was warmed slowly to 37° C. and gentlymixed to re-suspend. Activation buffer can be stored at room temperaturewith no loss in activity.

Reaction buffer: The buffer was kept at 4° C. while in use.

AlphaScreen® Protein A IgG Kit: The kit was stored at 4° C. in the dark.

Reaction buffer+Activation buffer+AlphaScreen® Acceptor beads: Reactionbuffer (40 parts), Activation Buffer (10 parts) and Acceptor beads (1part) were mixed and the mixture was stored at room temperature and usedthe same day. Mixture was added to 384-well plates; excess mixture wasdiscarded.

Dilution buffer+AlphaScreen® Donor beads: Dilution buffer (20 parts) andDonor beads (1 part) were mixed and the mixture was stored at roomtemperature and used the same day. Excess mixture was discarded.

Assay control samples: After reconstitution in 250 μl of water, lysateswere at −20° C. in single use aliquots.

Step B: Preparation of Samples and Cells

96-well Assay Protocol for 293FT and RMS13 adherent cells can be carriedout manually or in high throughput with liquid handling robots.

The cells (80 μL, of cells for 96 well plates) were plated in collagencoated tissue culture plates in RPMI or FreeStyle medium (Invitrogen)and incubated overnight. For manual analysis, 6 plates for GDF8, 6plates for TGFβ, and optionally 6 plates for Alk5ca (ALK5 constitutivelyactive) were used.

The compound dilution plates were prepared as follows: 12 μL of DMSO wastransferred into first column of 96-well plate, and 16 μL of DMSO wastransferred into columns 2-12 of the 96-well plate. 12 μL of compoundsolution was transferred into first column of the DMSO-containing96-well plate. Three-fold dilution was performed up to column 10 of theDMSO-containing 96-well plate.

Step C: Treatment and Analysis

The plate containing cells were treated with compounds for about 10minutes, and then ligand was added. GDF8 or TGFb was added to plates tostimulate. 293FL cells were stimulated for 90 minutes at 37° C.; andRMS13 cells were stimulated for 60 minutes at 37° C. The medium was thenremoved from the cells, and 1× Lysis Buffer (about 25 μL) was added andthe plate was gently agitated on plate shaker for 5-10 minutes.

The lysate (5 μL) was then placed into 384-well shallow plates avoidingthe generation of bubbles. To this, the Reaction Buffer+ActivationBuffer+AlphaScreen® Acceptor beads mixture (5 μL) was added. The platewas sealed with adhesive cover and shielded from light (e.g., with metalfoil), and agitated gently on plate shaker for 2 hours at roomtemperature.

Dilution buffer+AlphaScreen® Donor beads (2 μL) was then added, and theplate was intubated on the plate shaker for an additional 1½ hours.After completion, the plate was read on Synergy-4 or Enspire platereader, using AlphaScreen® pSMAD3® settings.

Representative results for inhibition of GDF8 signaling are shown inTable 2:

GDF pSMAD (MPC11) Cmpd # μM 1 1.654 2 —* 3 1.296 4 — 5 — 6 18.65 7 23.118 5.349 9 5.135 10 0.5349 11 0.5945 12 18.89 13 — 14 — 15 0.0649 16 6.3417 0.3358 18 0.1419 19 0.083 20 0.1037 21 1.917 22 1.414 23 2.245 240.6713 25 0.6123 26 0.8118 27 0.4527 28 1.754 29 1.446 30 3.704 31 1.89932 2.796 33 5007 34 8.832 35 10.78 36 19.71 37 18.1 38 3.227 39 14.33 4018.47 41 3.136 42 10.49 43 1.621 44 — 45 — 46 1.73 47 8.229 48 8.379 49— 50 — 51 5.441 52 1.398 53 13.37 54 — 55 — 61 3.882 62 0.8036 63 0.141564 0.8396 65 2.238 66 1.784 67 1.807 68 0.1865 69 5005 70 5.703 71 7.01272 5014 73 0.4969 74 — 75 3.468 76 1.815 77 3.65 78 0.3157 79 0.2636 806.333 81 — 82 — 83 — 84 — 85 — 86 — 87 — 88 — 89 2.551 90 2.612 91 3.02892 — 93 4.835 94 — 95 — 96 — 97 — 98 10.34 99 0.8936 100 6.034 101 11.24102 0.3408 103 — 104 — 105 — 106 — 107 — 108 — 109 17.19 110 — 111 — 1120.2733 113 — 114 — 115 — 116 0.0326 117 0.1786 118 3.785 119 — 1200.3635 121 5.348 122 4.037 123 — 124 0.5478 125 — 126 — 127 — 128 — 129— 130 — 131 — 132 — 133 — 134 — 135 — 136 — 137 22.83 138 4.331 1393.371 140 2.886 141 18.57 142 1.192 143 12.16 144 9.39 145 1.127 1460.6209 147 — 148 — 149 0.6418 150 0.2085 151 0.678 152 0.0487 153 0.4504154 1.306 155 0.2236 156 1.789 157 1.564 158 1.859 159 0.1304 160 0.0843161 9.101 162 5.664 163 — 164 — 165 0.2646 166 0.1093 167 17.46 168 —169 — 170 1.959 171 — 172 0.1874 173 1.827 174 1.176 175 0.1181 1760.057 177 0.3629 178 0.187 179 0.3368 180 0.4224 181 0.5391 182 — 183 —184 12.92 185 8.86 186 0.2996 187 0.2282 188 — 189 — 190 1.551 1910.6629 192 0.3473 193 0.2432 194 0.1494 195 9.52 196 — 197 0.3588 1980.44 199 1.164 200 0.2601 201 — 207 2.039 208 1.146 209 18.25 210 12.72211 0.1979 212 18.39 213 4.437 214 2.642 215 15.67 216 0.7365 217 0.8413218 0.4459 219 6.766 220 8.62 221 — 222 5.623 223 0.7071 224 0.6209 2259.457 226 10.04 227 — 228 9.762 229 — 230 10.77 231 10.81 232 10.64 2336.691 234 — 235 — 236 — 237 — 238 — 239 0.2662 240 7.454 241 4.056 242 —243 11.89 244 0.7979 245 1.257 246 1.29 247 3.197 248 5007 249 8.832 25010.46 251 17.81 252 12.65 253 12.38 254 0.3904 255 — 256 — 257 1.84 2581.267 259 5007 260 — 261 — 262 — 263 — 264 9.152 265 8.122 266 4.535 2676.757 268 14.41 269 1.383 270 — 271 4.444 272 3.401 273 9.786 274 14.77275 2.948 276 — 277 1.671 278 2.226 279 — 280 — 281 1.304 282 19.38 28317.72 284 — 285 — 286 11.96 287 3.03 288 — 289 — 290 — 291 1.231 2921.739 293 5.541 294 — 295 — 296 — 297 2.26 298 0.9992 299 1.2 300 12.79301 0.3451 302 0.7949 303 0.0947 304 0.0853 305 0.1751 306 0.1294 3072.222 308 4.809 309 1.475 310 1.143 311 4.719 312 7.538 313 5009 3145.345 315 0.7489 316 6.389 317 5.5 318 1.305 319 10.63 320 2.993 3210.6792 322 0.2531 323 0.327 324 0.4612 325 0.1865 326 0.1983 327 0.3234328 2.497 329 0.8032 330 0.4565 331 1.329 332 0.3115 333 0.3764 3340.3727 335 0.306 336 0.7635 337 0.4792 338 0.1639 339 0.5903 340 0.4637341 0.2595 342 0.1058 343 2.644 344 — 345 4.83 346 0.1933 347 1.493 3481.303 349 1.009 350 0.3473 351 0.2151 352 0.3069 353 0.6888 354 1.27 355— 356 0.9646 357 — 358 0.8629 359 0.5243 360 5.669 361 0.2296 362 0.1051363 0.9033 364 0.3383 365 0.1653 366 0.2258 367 0.2799 368 0.1894 3690.1933 370 0.4111 371 0.7368 372 0.3387 373 1.2 374 0.4949 375 0.1524376 0.276 377 0.1724 378 0.5583 379 0.3954 380 18.51 381 2.607 382 14.8383 16.74 384 7.792 385 2.557 386 2.004 387 1.279 388 0.5469 389 0.1871390 0.5164 391 0.2278 392 0.1274 393 0.07 394 0.1191 395 0.9586 3960.2083 397 9.407 398 3341 399 4.653 400 5.806 401 5.891 402 5000 4031.666 404 1.029 405 10.69 406 2.794 407 2.467 408 0.6732 409 7.954 4104.13 411 0.0725 412 — 413 — 414 3.334 415 11.8 416 4.858 417 — 418 — 419— 420 — 421 1.401 422 1.275 423 0.6277 424 2.426 425 0.5369 426 — 427 —428 — 429 0.3842 430 0.4748 431 0.3736 432 0.5131 433 0.2851 434 1.491435 0.608 436 1.18 437 0.7391 438 0.9588 439 0.7381 440 1.863 441 1.156442 0.3659 443 0.429 444 1.081 445 0.5146 446 0.3975 447 0.7534 4480.1368 449 0.0686 450 0.1358 451 0.1151 452 0.2231 453 0.8161 454 0.9262455 1.163 456 0.2988 457 5005 458 3333 459 11.48 460 0.1291 461 0.5511462 18.41 463 0.2966 464 3.96 465 10.26 466 7.583 467 12.19 468 7.824469 1.58 470 21.11 471 — 472 — 473 0.2925 474 0.4292 475 — 476 2.756 4770.4919 478 6.604 479 — 480 1.213 481 1.285 482 1.698 483 0.8197 4840.1606 485 — 486 — 487 — 488 — 489 — 490 6.51 491 9.218 492 3.729 4930.9379 494 0.1069 495 0.2471 496 0.7833 497 9.222 498 1.197 499 6.521500 — 501 0.3552 502 0.5629 503 4.816 504 4.96 505 — 506 1.832 507 3.365508 — 509 0.2652 510 — 511 — 512 — 513 — 514 — 515 — 516 — 517 1.166 518— 519 — 520 — 521 8.061 522 — 523 5006 524 5007 525 — 526 527 0.1369 5280.1751 529 0.3228 530 0.6247 531 11.23 532 17.67 533 6.118 534 18 5350.5038 536 0.4043 537 0.1106 538 0.4739 539 0.6993 540 0.4264 541 0.2497542 1.717 543 — 544 — 545 — 546 — 547 — 548 16.4 549 5.006 550 — 5514.883 552 4.058 553 3.241 554 4.683 555 0.1564 556 0.3633 557 0.4389 5580.1875 559 0.1616 560 2.477 561 10.96 562 9.784 563 5.199 564 18.35 5650.406 566 0.342 567 0.2253 568 0.6745 569 5.414 570 5.903 571 7.312 572— 573 1.214 574 0.8526 575 1.166 576 3.691 577 2.257 578 2.229 579 12.38580 8.455 581 6.308 582 0.4936 583 0.5178 584 0.0962 585 0.5103 5860.6169 587 0.3662 588 0.3164 589 1.223 590 0.5137 591 0.3331 592 0.2046593 1.859 594 0.5704 595 1.159 596 0.2038 597 0.8369 598 2.046 599 3.883600 0.1788 601 0.1409 602 0.0681 603 0.1093 604 8.522 605 7.936 6061.439 607 0.7054 608 0.3258 609 0.3188 610 0.6479 611 0.1141 612 0.408613 0.6236 614 5.558 615 2.129 616 2.185 617 10.8 618 1.12 619 0.5439620 621 3.926 622 3.63 623 6.867 624 0.1605 625 7.793 626 0.3457 6271.255 628 1.707 629 0.1318 630 4.152 631 — 632 — 633 11.34 634 14.75 635— 636 8.691 637 — 638 — 639 10.56 640 19.18 641 642 643 644 645 646 647648 649 650 651 1.18 652 3.777 653 1.037 654 0.5532 655 0.2453 6560.5499 657 3.488 658 1.501 659 2.007 660 2.243 661 1.842 662 9.637 6638.093 664 1.382 665 2.36 666 3.973 667 0.2261 668 0.3134 669 0.4992 6700.3666 671 — 672 0.2727 673 0.3747 674 0.2109 675 0.2268 676 0.2668 6770.5621 678 2.472 679 10.82 680 2.133 681 0.2881 682 0.5389 683 0.2336684 0.5928 685 0.1499 686 0.2054 687 0.1722 688 1.263 689 0.5163 6900.4136 691 0.4468 692 0.4361 693 0.5073 694 0.7936 695 1.517 696 2.106697 0.4147 698 0.145 699 2.301 700 0.1376 701 0.1671 702 0.8818 7030.2081 704 0.2805 705 0.1217 706 0.2275 707 0.2215 708 0.2659 709 0.2523710 1.218 711 9.278 712 4.057 713 10.2 714 5.662 715 2.03 716 5.026 7170.2169 718 0.3141 719 0.4018 720 0.8217 721 0.4398 722 0.0639 723 0.1017724 0.5366 725 0.4645 726 0.5654 727 0.8864 728 5.062 729 0.2864 7300.5898 731 0.5061 732 0.2577 733 1.273 734 0.6942 735 0.6762 736 0.2507737 0.2596 738 1.376 739 2.318 740 9.499 741 10.01 742 1.825 743 0.6383744 0.9677 745 0.3663 746 0.5661 747 0.2844 748 0.4473 749 0.2982 750 —751 — 752 — 753 — 754 — 755 — 756 0.3644 757 0.1274 758 0.4264 7590.1747 760 0.2742 761 0.1312 762 1.188 763 0.5199 764 0.2751 765 0.096766 0.1048 767 0.2267 768 0.3267 769 0.1533 770 1.309 771 1.107 7724.949 773 8.48 774 — 775 3.961 776 — 777 — 778 — 779 0.7609 780 0.7298781 5.864 782 0.3324 783 0.2309 784 0.1252 785 0.1103 786 0.3404 787 —788 4.042 789 — 790 4.991 791 5.372 792 2.433 793 2.082 794 1.798 7958.105 796 14 797 3.813 798 2.615 799 14.64 800 0.8792 801 — 802 5.828803 2.262 804 10.11 805 0.9533 806 — 807 5008 808 1.537 809 4 810 5.784811 2.924 812 2.142 813 2.43 814 — 815 0.9414 816 1.609 817 0.5839 8180.0774 819 0.1192 820 3.062 821 2.161 822 0.1272 823 0.2137 824 — 825 —826 — 827 — 828 — 829 — 830 — 831 — 832 — 833 — 834 — 835 — 836 5.937837 4.861 838 — 839 — 840 8.142 841 7.644 842 17.37 843 0.0213 8440.0324 845 0.0588 846 14.28 847 — 848 11.12 849 18.08 850 20.7 851 — 8520.2074 853 0.8812 854 4.666 855 3.442 856 5.585 857 1.854 858 2.367 8593.7 860 9.985 861 4.006 862 1.836 863 5.894 864 1.54 865 0.6077 8660.2506 867 0.752 868 0.4041 869 0.6883 870 0.557 871 1.828 872 0.7755873 1.193 874 6.466 875 12.41 876 2.374 877 — 878 10.22 879 1.477 8800.8077 881 — 882 1.124 883 0.5124 884 0.9974 885 — 886 0.2526 887 1.746888 4.054 889 1.519 890 1.296 891 0.6324 892 0.426 896 0.0936 897 — 8980.7137 899 2.144 900 2.346 901 1.065 902 — 903 2.584 904 9.071 905 1.489906 3.339 907 0.1635 908 — 909 — 910 0.0972 911 0.0939 912 0.112 9130.6611 914 0.126 915 0.5578 916 0.1035 917 0.1804 918 0.2063 919 — 9200.272 921 0.0706 922 — 923 — 924 — 925 — 926 — 927 — 928 — 929 — 930 —931 — 932 — 933 — 934 0.4097 935 0.1918 936 0.2281 937 0.2072 938 0.2419939 — 940 — 941 — 942 — 943 — 944 — 945 — 946 — 947 0.4288 948 0.9508949 0.3754 950 0.129 951 0.5429 952 0.3911 953 0.6607 954 0.4381 9550.2901 956 0.4211 957 — 958 — 959 — 960 1.685 961 0.129 962 0.622 9630.1751 964 0.2315 965 5.188 966 — 967 1.44 *The notation “—” indicatesthat the compound was tested but did not have measurable activity inthis assay.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be incorporated within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated herein by referencefor all purposes.

We claim:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein X is N; R¹ ishalogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R¹⁰, or—C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR^(a)R^(a), —C(O)R, —C(O)OR,—C(O)NR^(a)R^(a), —S(O)₂NR^(a)R^(a), —OC(O)R, —N(R)C(O)R, —OC(O)OR,—O(CH₂)_(m)C(O)NR^(a)R^(a), —N(R)C(O)OR, —N(R)C(O)NR^(a)R^(a),—N(R)S(O)₂NR^(a)R^(a) or —N(R)S(O)₂R; R² is hydrogen, halogen, cyano,nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,heterocyclyl, aryl, heteroaryl, —R¹⁰, or —C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is—OR, —SR, —NR^(a)R^(a), —C(O)R, —C(O)OR, —C(O)NR^(a)R^(a),—S(O)₂NR^(a)R^(a), —OC(O)R, —N(R)C(O)R, —OC(O)OR,—O(CH₂)_(m)C(O)NR^(a)R^(a), —N(R)C(O)OR, —N(R)C(O)NR^(a)R^(a),—N(R)S(O)₂NR^(a)R^(a) or —N(R)S(O)₂R; or when R¹ and R² are attached toadjacent carbon atoms they are optionally taken together with the atomsto which they are attached to form a 5- or 6-membered ring optionallysubstituted with one or two groups that are each independently halogen,oxo, oxime, imino, C₁₋₆alkyl, C₁₋₆haloalkyl, or R¹⁰; each R^(a) isindependently R or, two R^(a) together with the nitrogen atom to whichthey are attached form a 3-8 membered heterocyclyl group, optionallyincluding 1-4 additional heteroatoms selected from O, N and S andoptionally substituted with 1-4 R groups; each R^(b) is independentlyhalogen, cyano, oxo, C₁₋₆alkyl, C₁₋₆haloalkyl, or —OR; m is 0, 1 or 2; nis 1, 2, 3 or 4; R⁵ and R⁶ are each independently hydrogen, halogen,C₁₋₆alkyl optionally substituted with 1-3 R^(b), C₁₋₆haloalkyl,C₃₋₈cycloalkyl optionally substituted with one or two R^(b), heteroaryloptionally substituted with one or two R^(b), aryl optionallysubstituted with one or two R^(b), heterocyclyl(C₁₋₆alkyl) optionallysubstituted with one or two Rb, —OR, —SR, —NR^(a)R^(a), —OC(O)R,—C(O)NR^(a)R^(a), —OC(O)NR^(a)R^(a), —C(O)OR, —N(R)C(O)R, —N(R)S(O)₂R,or R⁵ and R⁶ are optionally taken together with the atoms to which theyare attached to form a 5- or 6-membered ring optionally including 1-3additional heteroatoms selected from O, N and S and optionallysubstituted with 1-4 Rb; Z is (a) a fused bicyclic ring of the formula,

wherein ring A is a phenyl or 5- or 6-membered heteroaryl, ring B is a5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl; or (b)pyridinyl or pyrimidinyl, wherein Z is optionally substituted by one ortwo groups that are each independently halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl),heteroaryl(C₁₋₆alkyl), —R^(Z), or —C₁₋₆alkyl-R^(Z), wherein theC₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), andheteroaryl(C₁₋₆alkyl) are each optionally substituted by one or twogroups that are each independently halogen, C₁₋₆alkyl, or R^(Z); andR^(Z) is cyano, —CF₃, —OR, —SR, —NR^(a)R^(a), —C(O)R, —C(O)OR,—C(O)NR^(a)R^(a), —S(O)₂NR^(a)R^(a), —S(O)₂R⁰, —OC(O)R, —N(R)C(O)R,—OC(O)OR, —OC(O)NR^(a)R^(a), —N(R)C(O)OR, —N(R)C(O)NR^(a)R^(a),—N(R)S(O)₂R, or —OP(O)(OR)₂; or Z is (c) phenyl substituted with 1, 2,3, 4, or 5 groups that are each independently a halogen; wherein each Ris independently hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocyclyl, aryl, heteroaryl, heteroaryl(heteroaryl)-,heterocyclyl(aryl)-, heteroaryl(heterocyclyl)-,C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), orheteroaryl(C₁₋₆alkyl), each optionally substituted by 1-5 groups thatare each independently R^(b), —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰,—C(O)N(R⁰)₂, —S(O)₂N(R⁰)₂, —OC(O)R⁰, —N(R⁰)C(O)R⁰, —OC(O)OR⁰,—O(CH₂)_(m)C(O)N(R⁰)₂, —N(R⁰)C(O)OR⁰, —N(R⁰)C(O)N(R⁰)₂, or —N(R⁰)S(O)₂R⁰and each R⁰ is independently hydrogen, C₁₋₆haloalkyl, C₁₋₆alkyloptionally substituted with 1-3 R^(b), C₃₋₈cycloalkyl optionallysubstituted with one or two R^(b) or, alternatively two R⁰ together witha nitrogen atom to which they are bound form a 3-8 membered heterocyclylgroup, optionally including 1-4 additional heteroatoms selected from O,N and S and optionally substituted with 0-3 R^(b) and R groups.
 2. Thecompound or pharmaceutically acceptable salt of claim 1 of the formula,


3. The compound or pharmaceutically acceptable salt of claim 1, whereinR¹ is halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R¹⁰, or—C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)NR₂, or —N(R)S(O)₂R, and R² is hydrogen, halogen,cyano, nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R¹⁰, or—C₁₋₆alkyl-R¹⁰, wherein R¹⁰ is —OR, —SR, —NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —S(O)₂NR₂, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)NR₂, or —N(R)S(O)₂R.
 4. The compound orpharmaceutically acceptable salt of claim 1, wherein R¹ is halogen, orC₁₋₆alkyl, and R² is hydrogen, halogen, or C₁₋₆alkyl.
 5. The compound orpharmaceutically acceptable salt of claim 1, wherein R¹ is fluoro and R²is methyl.
 6. The compound or pharmaceutically acceptable salt of claim1, wherein ring A is a phenyl or pyridyl ring.
 7. The compound orpharmaceutically acceptable salt of claim 1, wherein Z is of theformula,

wherein each is optionally substituted by one or two groups that areeach independently halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocyclyl, aryl, heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), heteroaryl(C₁₋₆alkyl), —R^(Z),or —C₁₋₆alkyl-R^(Z), wherein the C₃₋₈cycloalkyl, heterocyclyl, aryl,heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),aryl(C₁₋₆alkyl), and heteroaryl(C₁₋₆alkyl) are each optionallysubstituted by one to four groups that are each independently C₁₋₆alkylor —R^(Z).
 8. The compound or pharmaceutically acceptable salt of claim1, wherein Z is of the formula,

wherein each is optionally substituted by one or two groups that areeach independently halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocyclyl, aryl, heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl),heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), heteroaryl(C₁₋₆alkyl), —R^(Z),or —C₁₋₆alkyl-R^(Z), wherein the C₃₋₈cycloalkyl, heterocyclyl, aryl,heteroaryl, C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl),aryl(C₁₋₆alkyl), and heteroaryl(C₁₋₆alkyl) are each optionallysubstituted by one to four groups that are each independently C₁₋₆alkylor —R^(Z).
 9. The compound or pharmaceutically acceptable salt of claim1, wherein Z is

wherein R^(Z1) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, or—C₁₋₆alkyl-R^(Z); and R^(Z2) is hydrogen, halogen, or C₁₋₆alkyl.
 10. Thecompound or pharmaceutically acceptable salt of claim 1, wherein Z is

wherein Q is —O—, —S—, or —N(R^(Z1))—; and R^(Z1) is hydrogen,C₁₋₆alkyl, C₁₋₆haloalkyl, or —C₁₋₆alkyl-R^(Z); and R^(Z2) is hydrogen,halogen, or C₁₋₆alkyl.
 11. The compound or pharmaceutically acceptablesalt of claim 1, wherein Z is phenyl substituted with 1, 2, 3, 4, or 5groups that are each independently halogen.
 12. The compound orpharmaceutically acceptable salt of any one of claim 1, wherein Z ispyridinyl or pyrimidinyl optionally substituted by one or two groupsthat are each independently halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl),heteroaryl(C₁₋₆alkyl), —R^(Z), or —C₁₋₆alkyl-R^(Z), wherein theC₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl,C₃₋₈cycloalkyl(C₁₋₆alkyl), heterocyclyl(C₁₋₆alkyl), aryl(C₁₋₆alkyl), andheteroaryl(C₁₋₆alkyl) are each optionally substituted by one or twogroups that are each independently halogen, C₁₋₆alkyl, or —R^(Z); andR^(Z) is cyano, —CF₃, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NR^(a)R^(a),—S(O)₂NR^(a)R^(a), —S(O)₂R⁰, —OC(O)R, —N(R)C(O)R, —OC(O)OR,—OC(O)NR^(a)R^(a), —N(R)C(O)OR, —N(R)C(O)NR^(a)R^(a), —N(R)S(O)₂R, or—OP(O)(OR)₂.
 13. The compound of claim 1 that is5-(2-(6-Methylpyridin-2-yl)pyridin-3-yl)-1H-indazole;2′-(Benzo[d][1,3]dioxol-5-yl)-6-methyl-2,3′-bipyridine;6-(6-Methyl-[2,3′-bipyridin]-2′-yl)quinoxaline;5-(6-Methyl-[2,3′-bipyridin]-2′-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;6-(6-Methyl-[2,3′-bipyridin]-2′-yl)-1H-benzo[d]imidazole;6-(6-Methyl-[2,3′-bipyridin]-2′-yl)isoquinoline.
 14. A pharmaceuticalcomposition comprising a compound or pharmaceutically acceptable saltaccording to claim 1 and a pharmaceutically acceptable carrier,excipient, or diluent.